OLIGONUCLEOTIDES TO INDUCE PATERNAL EXPRESSION OF UBE3A

Abstract

This patent application relates to a method for determining the in vitro efficacy profile of a drug candidate using standardized cell cultures of uniformly distributed differentiated neural cells (NCs) from at least two primate species. The differentiated NC cultures are qualified for high-throughput screening. The method involves a dissociation and reseeding step performed on the differentiated NCs. The method comprises differentiating neuronal precursor cells (NPCs) from human and / or non-human primate neurons into neuronal cells (NCs), followed by dissociating the differentiated NCs from their substrate and reseeding them in a high-throughput cell culture format to obtain robust cultures suitable for high-throughput drug screening, particularly for screening antisense oligonucleotides.

Description

FIELD OF INVENTION

[0001] The present invention relates to oligonucleotides (oligomers) that are complementary to and hybridize to SNHG14 downstream of SNORD109B, leading to induction of paternal expression of Ubiquitin-protein ligase E3A (UBE3A) in an animal or human. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.BACKGROUND

[0002] Angelman syndrome is neuro-genetic disorder caused by deletion or inactivation of the UBE3A genes on the maternally inherited chromosome 15q11.2. The paternal copy of the UBE3A gene is subject to genomic imprinting and silencing in neurons by an endogenous antisense transcript of UBE3A, termed SNHG14 (also known as UBE3A-ATS) (Meng et al. 2012 Hum Mol Genet. Vol. 21 pp. 3001-12). Other cell types than neurons seem to express the UBE3A gene from both the maternal and paternal allele.

[0003] Angelman syndrome is characterized by severe intellectual and developmental disability, sleep disturbance, seizures, jerky movements, EEG abnormalities, frequent laughter or smiling, and profound language impairments.

[0004] WO 2012 / 064806 discloses a method of inducing UBE3A expression in a cell by using a topoisomerase inhibitor. The method can be used to treat Angelman syndrome. There is no disclosure of antisense oligonucleotides.

[0005] WO 2014 / 004572 discloses oligonucleotides with 2'-O-methoxyethyl-RNA (MOE) modifications targeting mouse UBE3A-ATS. The oligonucleotides are only tested in mice related assays. In the region downstream of MBII-52 snoRNA (also known as SNORD115) and upstream of the UBE3A pre-mRNA there is no conservation between mouse and human.Oligonucleotides targeting mouse UBE3A-ATS can therefore not be translated into oligonucleotides that will function in a human. There is no disclosure of oligonucleotides targeting human UBE3A-ATS.OBJECTIVE OF THE INVENTION

[0006] The present invention identifies novel oligonucleotides which induce human paternal UBE3A expression in neuronal without affection expression of the paternal SNORD115, SNORD116 and SNRPN transcripts significantly.SUMMARY OF INVENTION

[0007] In one aspect the present invention is an antisense oligonucleotide wherein the oligonucleotide is the oligonucleotide compound TTAcActtaattatactTCC (CMP ID NO: 626_7) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

[0008] In a further aspect the present invention is a pharmaceutical composition comprising the oligonucleotide of the present invention and a pharmaceutically acceptable diluent, solvent, carrier, salt and / or adjuvant.

[0009] In a further aspect the present invention is a pharmaceutical composition of the present invention for use as a medicament.

[0010] In a further aspect the present invention is an in vitro method for inducing UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering an oligonucleotide of the present invention or the pharmaceutical composition of any one of the present invention in an effective amount to said cell.

[0011] In a further aspect, the present invention is the oligonucleotide of the present invention or the pharmaceutical composition of the present invention for use in the treatment or prevention of Angelman syndrome.

[0012] The present invention relates to oligonucleotides targeting a nucleic acid capable of supressing the expression of UBE3A and to treat or prevent diseases related to decreased activity of UBE3A, in particular in neuronal cells.

[0013] Described herein are oligonucleotides which comprise a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 98% complementarity to the part of human SNHG14 long non-coding RNA corresponding to position 25278410 to 25419462 on human chromosome 15 version GRCh38.p2. This region is also resembled by SEQ ID NO: 1. The oligonucleotide can be an antisense oligonucleotide, preferably with a gapmer design. Preferably, the oligonucleotide is capable of inducing the expression of UBE3A, in particular paternal UBE3A expression in a neuron, by degradation, reduction or removal of the UBE3A suppressor, in particular by reduction of the SNHG14 long non-coding RNA transcript downstream of SNORD109B. The UBE3A re-expression is achieved, without significantly affecting the expression of SNORD115. The degradation of the target nucleic acid is preferably achieved via nuclease recruitment.

[0014] In a further aspect, the invention provides pharmaceutical compositions comprising the oligonucleotide of the invention and pharmaceutically acceptable diluents, carriers, salts and / or adjuvants.

[0015] Described herein are methods for in vivo or in vitro induction of UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, by administering an oligonucleotide or composition of the invention in an effective amount to said cell.

[0016] Described herein are methods for treating or preventing a disease, disorder or dysfunction associated with in vivo activity of UBE3A comprising administering a therapeutically or prophylactically effective amount of the oligonucleotide of the invention to a subject suffering from or susceptible to the disease, disorder or dysfunction.

[0017] In a further aspect the oligonucleotide or composition of the invention is used for the treatment or prevention of Angelman syndrome.BRIEF DESCRIPTION OF FIGURES

[0018] Figure 1: The upper strand illustrates the region of the SNHG14 transcript downstream of SNORD109B (UBE3A-ATS) where the black boxes indicate the location of the tested mouse oligonucleotides. The lower strand illustrates the UBE3A coding region, where the black boxes indicate exons. Exon 1 is located around 160kb. The oligonucleotides are placed in the antisense region of Exon 9 (positioned at ∼97kb), Exon 10 (positioned at ∼92kb), Exon 13 (positioned at ∼77kb) and the 5' end of Exon 16 (positioned at ∼60kb). Figure 2: Representation of the ability of the oligonucleotides, tested in Example 2, to induce re-expression of UBE3A in human neuronal cell cultures. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA between SNORD109B and the region upstream of the UBE3A coding region (position 1 to 55318 of SEQ ID NO: 1) are indicated with • nonoverlap. Oligonucleotides complementary to the region of human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (position 55319 to 141053 of SEQ ID NO: 1) are indicated with ▲overlap. Oligonucleotides from Table 3 with conservation to human and rhesus monkey are indicated at the bottom of each plot as . Conservation between human:rhesus:mouse is indicated by . The oligonucleotide concentrations were 0.2, 1 and 5 microM as indicated in the right hand side each plot. DEFINITIONS Oligonucleotide

[0019] The term "oligonucleotide" as used herein is defined as it is generally understood by the skilled person as a molecule comprising two or more covalently linked nucleosides. Such covalently bound nucleosides may also be referred to as nucleic acid molecules or oligomers. Oligonucleotides are commonly made in the laboratory by solid-phase chemical synthesis followed by purification. When referring to a sequence of the oligonucleotide, reference is made to the sequence or order of nucleobase moieties, or modifications thereof, of the covalently linked nucleotides or nucleosides. The oligonucleotide of the invention is man-made, and is chemically synthesized, and is typically purified or isolated. The oligonucleotide of the invention may comprise one or more modified nucleosides or nucleotides.Antisense oligonucleotides

[0020] The term "Antisense oligonucleotide" as used herein is defined as oligonucleotides capable of modulating expression of a target gene by hybridizing to a target nucleic acid, in particular to a contiguous sequence on a target nucleic acid. The antisense oligonucleotides are not essentially double stranded and are therefore not siRNAs. Preferably, the antisense oligonucleotide of the present invention is single stranded.Contiguous Nucleotide Sequence

[0021] The term "contiguous nucleotide sequence" refers to the region of the oligonucleotide which is complementary to the target nucleic acid. The term is used interchangeably herein with the term "contiguous nucleobase sequence" and the term "oligonucleotide motif sequence". In some embodiments all the nucleotides of the oligonucleotide are present in the contiguous nucleotide sequence. In some embodiments the oligonucleotide comprises the contiguous nucleotide sequence and may, optionally comprise further nucleotide(s), for example a nucleotide linker region which may be used to attach a functional group to the contiguous nucleotide sequence. The nucleotide linker region may or may not be complementary to the target nucleic acid.Nucleotides

[0022] Nucleotides are the building blocks of oligonucleotides and polynucleotides, and for the purposes of the present invention include both naturally occurring and non-naturally occurring nucleotides. In nature, nucleotides, such as DNA and RNA nucleotides comprise a ribose sugar moiety, a nucleobase moiety and one or more phosphate groups (which is absent in nucleosides). Nucleosides and nucleotides may also interchangeably be referred to as "units" or "monomers".Modified nucleoside

[0023] The term "modified nucleoside" or "nucleoside modification" as used herein refers to nucleosides modified as compared to the equivalent DNA or RNA nucleoside by the introduction of one or more modifications of the sugar moiety or the (nucleo)base moiety. The modified nucleoside comprises a modified sugar moiety. The term modified nucleoside may also be used herein interchangeably with the term "nucleoside analogue" or modified "units" or modified "monomers".Modified internucleoside linkage

[0024] The term "modified internucleoside linkage" is defined as generally understood by the skilled person as linkages other than phosphodiester (PO) linkages, that covalently couples two nucleosides together. Nucleotides with modified internucleoside linkage are also termed "modified nucleotides". In some embodiments, the modified internucleoside linkage increases the nuclease resistance of the oligonucleotide compared to a phosphodiester linkage. For naturally occurring oligonucleotides, the internucleoside linkage includes phosphate groups creating a phosphodiester bond between adjacent nucleosides. Modified internucleoside linkages are particularly useful in stabilizing oligonucleotides for in vivo use, and may serve to protect against nuclease cleavage at regions of DNA or RNA nucleosides in the oligonucleotide of the invention, for example within the gap region of a gapmer oligonucleotide, as well as in regions of modified nucleosides.

[0025] As described herein, the oligonucleotide comprises one or more internucleoside linkages modified from the natural phosphodiester to a linkage that is for example more resistant to nuclease attack. Nuclease resistance may be determined by incubating the oligonucleotide in blood serum or by using a nuclease resistance assay (e.g. snake venom phosphodiesterase (SVPD)), both are well known in the art. Internucleoside linkages which are capable of enhancing the nuclease resistance of an oligonucleotide are referred to as nuclease resistant internucleoside linkages. As described herein at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are modified. It will be recognized that, in some embodiments the nucleosides which link the oligonucleotide of the invention to a non-nucleotide functional group, such as a conjugate, may be phosphodiester. As described herein all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are nuclease resistant internucleoside linkages.

[0026] Modified internucleoside linkages may be selected from the group comprising phosphorothioate, diphosphorothioate and boranophosphate. As described herein, the modified internucleoside linkages are compatible with the RNaseH recruitment of the oligonucleotide of the invention, for example phosphorothioate, diphosphorothioate or boranophosphate.

[0027] As described herein the internucleoside linkage comprises sulphur (S), such as a phosphorothioate internucleoside linkage.

[0028] A phosphorothioate internucleoside linkage is particularly useful due to nuclease resistance, beneficial pharmakokinetics and ease of manufacture. As described herein at least 50% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate, such as at least 60%, such as at least 70%, such as at least 80 or such as at least 90% of the internucleoside linkages in the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate. In some embodiments all of the internucleoside linkages of the oligonucleotide, or contiguous nucleotide sequence thereof, are phosphorothioate.

[0029] As described herein, the oligonucleotide comprises one or more neutral internucleoside linkage, particularly a internucleoside linkage selected from phosphotriester, methylphosphonate, MMI, amide-3, formacetal or thioformacetal.

[0030] Further internucleoside linkages are disclosed in WO2009 / 124238. As described herein the internucleoside linkage is selected from linkers disclosed in WO2007 / 031091. Particularly, the internucleoside linkage may be selected from -O-P(O) 2 -O-, -O-P(O,S)-O-, -O-P(S) 2 -O-, -S-P(O) 2 -O-, -S-P(O,S)-O-, -S-P(S) 2 -O-, -O-P(O) 2 -S-, -O-P(O,S)-S-, -S-P(O) 2 -S-, -O-PO(R H< )-O-, 0-PO(OCH 3 )-O-, -O-PO(NR H< )-O-, -O-PO(OCH 2 CH 2 S-R)-O-, -O-PO(BH 3 )-O-, -O-PO(NHR H< )-O-, -OP(O) 2 -NR H< -, -NR H< -P(O) 2 -O-, -NR H< -CO-O-, -NR H< -CO-NR H< -, and / or the internucleoside linker may be selected form the group consisting of: -O-CO-O-, -O-CO-NR H< -, -NR H< -CO-CH 2 -, -O-CH 2 -CO-NR H< -, -O-CH 2 -CH 2 -NR H< -, -CO-NR H< -CH 2 -, -CH 2 -NR H< CO-, -O-CH 2 -CH 2 -S-, -S-CH 2 -CH 2 -O-, -S-CH 2 -CH 2 -S-, -CH 2 -SO 2 -CH 2 -, -CH 2 -CO-NR H< -, -O-CH 2 -CH 2 -NR H< -CO-, -CH 2 -NCH 3 -O-CH 2 -, where R H< is selected from hydrogen and C1 -4-alkyl.

[0031] Nuclease resistant linkages, such as phosphothioate linkages, are particularly useful in oligonucleotide regions capable of recruiting nuclease when forming a duplex with the target nucleic acid, such as region G for gapmers, or the non-modified nucleoside region of headmers and tailmers. Phosphorothioate linkages may, however, also be useful in non-nuclease recruiting regions and / or affinity enhancing regions such as regions F and F' for gapmers, or the modified nucleoside region of headmers and tailmers.

[0032] Each of the design regions may however comprise internucleoside linkages other than phosphorothioate, such as phosphodiester linkages, in particularly in regions where modified nucleosides, such as LNA, protect the linkage against nuclease degradation. Inclusion of phosphodiester linkages, such as one or two linkages, particularly between or adjacent to modified nucleoside units (typically in the non-nuclease recruiting regions) can modify the bioavailability and / or bio-distribution of an oligonucleotide - see WO2008 / 113832.

[0033] As described herein all the internucleoside linkages in the oligonucleotide are phosphorothioate and / or boranophosphate linkages. Preferably, all the internucleoside linkages in the oligonucleotide are phosphorothioate linkages.Nucleobase

[0034] The term nucleobase includes the purine (e.g. adenine and guanine) and pyrimidine (e.g. uracil, thymine and cytosine) moiety present in nucleosides and nucleotides which form hydrogen bonds in nucleic acid hybridization. In the context of the present invention the term nucleobase also encompasses modified nucleobases which may differ from naturally occurring nucleobases, but are functional during nucleic acid hybridization. In this context "nucleobase" refers to both naturally occurring nucleobases such as adenine, guanine, cytosine, thymidine, uracil, xanthine and hypoxanthine, as well as non-naturally occurring variants. Such variants are for example described in Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1.

[0035] In a some embodiments the nucleobase moiety is modified by changing the purine or pyrimidine into a modified purine or pyrimidine, such as substituted purine or substituted pyrimidine, such as a nucleobased selected from isocytosine, pseudoisocytosine, 5-methyl cytosine, 5-thiozolo-cytosine, 5-propynyl-cytosine, 5-propynyl-uracil, 5-bromouracil 5-thiazolo-uracil, 2-thio-uracil, 2'thio-thymine, inosine, diaminopurine, 6-aminopurine, 2-aminopurine, 2,6-diaminopurine and 2-chloro-6-aminopurine.

[0036] The nucleobase moieties may be indicated by the letter code for each corresponding nucleobase, e.g. A, T, G, C or U, wherein each letter may optionally include modified nucleobases of equivalent function. For example, in the exemplified oligonucleotides, the nucleobase moieties are selected from A, T, G, C, and 5-methyl cytosine. Optionally, for LNA gapmers, 5-methyl cytosine LNA nucleosides may be used.Modified oligonucleotide

[0037] The term modified oligonucleotide describes an oligonucleotide comprising one or more sugar-modified nucleosides and / or modified internucleoside linkages. The term chimeric" oligonucleotide is a term that has been used in the literature to describe oligonucleotides with modified nucleosides.Complementarity

[0038] The term complementarity describes the capacity for Watson-Crick base-pairing of nucleosides / nucleotides. Watson-Crick base pairs are guanine (G)-cytosine (C) and adenine (A) - thymine (T) / uracil (U). It will be understood that oligonucleotides may comprise nucleosides with modified nucleobases, for example 5-methyl cytosine is often used in place of cytosine, and as such the term complementarity encompasses Watson Crick base-paring between non-modified and modified nucleobases (see for example Hirao et al (2012) Accounts of Chemical Research vol 45 page 2055 and Bergstrom (2009) Current Protocols in Nucleic Acid Chemistry Suppl. 37 1.4.1).

[0039] The term "% complementary" as used herein, refers to the number of nucleotides in percent of a contiguous nucleotide sequence in a nucleic acid molecule (e.g. oligonucleotide) which, at a given position, are complementary to (i.e. form Watson Crick base pairs with) a contiguous nucleotide sequence, at a given position of a separate nucleic acid molecule (e.g. the target nucleic acid). The percentage is calculated by counting the number of aligned bases that form pairs between the two sequences, dividing by the total number of nucleotides in the oligonucleotide and multiplying by 100. In such a comparison a nucleobase / nucleotide which does not align (form a base pair) is termed a mismatch.

[0040] The term "fully complementary", refers to 100% complementarity.Hybridization

[0041] The term "hybridizing" or "hybridizes" as used herein is to be understood as two nucleic acid strands (e.g. an oligonucleotide and a target nucleic acid) forming hydrogen bonds between base pairs on opposite strands thereby forming a duplex. The affinity of the binding between two nucleic acid strands is the strength of the hybridization. It is often described in terms of the melting temperature (T m ) defined as the temperature at which half of the oligonucleotides are duplexed with the target nucleic acid. At physiological conditions T m is not strictly proportional to the affinity (Mergny and Lacroix, 2003, Oligonucleotides 13:515-537). The standard state Gibbs free energy ΔG° is a more accurate representation of binding affinity and is related to the dissociation constant (K d ) of the reaction by ΔG°=-RTln(K d ), where R is the gas constant and T is the absolute temperature. Therefore, a very low ΔG° of the reaction between an oligonucleotide and the target nucleic acid reflects a strong hybridization between the oligonucleotide and target nucleic acid. ΔG° is the energy associated with a reaction where aqueous concentrations are 1M, the pH is 7, and the temperature is 37°C. The hybridization of oligonucleotides to a target nucleic acid is a spontaneous reaction and for spontaneous reactions ΔG° is less than zero. ΔG° can be measured experimentally, for example, by use of the isothermal titration calorimetry (ITC) method as described in Hansen et al., 1965, Chem. Comm. 36-38 and Holdgate et al., 2005, Drug Discov Today. The skilled person will know that commercial equipment is available for ΔG° measurements. ΔG° can also be estimated numerically by using the nearest neighbor model as described by SantaLucia, 1998, Proc Natl Acad Sci USA. 95: 1460-1465 using appropriately derived thermodynamic parameters described by Sugimoto et al., 1995, Biochemistry 34:11211-11216 and McTigue et al., 2004, Biochemistry 43:5388-5405. In order to have the possibility of modulating its intended nucleic acid target by hybridization, oligonucleotides of the present invention hybridize to a target nucleic acid with estimated ΔG° values below -10 kcal for oligonucleotides that are 10-30 nucleotides in length. In some embodiments the degree or strength of hybridization is measured by the standard state Gibbs free energy ΔG°. The oligonucleotides may hybridize to a target nucleic acid with estimated ΔG° values below the range of -10 kcal, such as below -15 kcal, such as below -20 kcal and such as below -25 kcal for oligonucleotides that are 8-30 nucleotides in length. In some embodiments the oligonucleotides hybridize to a target nucleic acid with an estimated ΔG° value of -10 to -60 kcal, such as -12 to -40, such as from -15 to -30 kcal or-16 to -27 kcal such as -18 to -25 kcal.The target

[0042] The target refers to the protein which it is desired to modulate.Target nucleic acid

[0043] A target nucleic acid is the intended target which the oligonucleotide of the invention hybridizes to, and may for example be a gene, a RNA, a non-coding RNA, a long non-coding RNA, a mRNA, and pre-mRNA, a mature mRNA or a cDNA sequence. In some embodiments the target nucleic acid is a non-coding RNA or a long non-coding RNA, or a subsequence thereof. For in vivo or in vitro application, the oligonucleotide of the invention is capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B of and thereby relieving the suppression of the paternal UBE3A transcript in the intended target cell. The contiguous sequence of nucleobases of the oligonucleotide of the invention is complementary to the target nucleic acid, as measured across the length of the oligonucleotide, optionally with the exception of one or two mismatches, and optionally excluding nucleotide based linker regions which may link the oligonucleotide to an optional functional group such as a conjugate.Target Sequence

[0044] The oligonucleotide comprises a contiguous nucleotide sequence which is complementary to or hybridizes to a sub-sequence of the target nucleic acid molecule. The term "target sequence" as used herein refers to a sequence of nucleotides present in the target nucleic acid which comprises the nucleobase sequence which is complementary to the oligonucleotide of the invention. In some embodiments, the target sequence consists of a region on the target nucleic acid which is complementary to the contiguous nucleotide sequence of the oligonucleotide of the invention. In some embodiments the target sequence is longer than the complementary sequence of a single oligonucleotide, and may, for example represent a preferred region of the target nucleic acid which may be targeted by several oligonucleotides of the invention.

[0045] The oligonucleotide of the invention comprises a contiguous nucleotide sequence which is complementary to the target nucleic acid, such as a target sequence.

[0046] The oligonucleotide comprises a contiguous nucleotide sequence of at least 8 nucleotides which is complementary to or hybridizes to a target sequence present in the target nucleic acid molecule. The contiguous nucleotide sequence (and therefore the target sequence) comprises of at least 8 contiguous nucleotides, such as 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides, such as from 12-25, such as from 14-18 contiguous nucleotides.Target Cell

[0047] The term a target cell as used herein refers to a cell which is expressing the target nucleic acid. As described herein the target cell may be in vivo or in vitro. In some embodiments the target cell is a mammalian cell such as a rodent cell, such as a mouse cell or a rat cell, or a primate cell such as a monkey cell or a human cell. In preferred embodiments the target cell is a neuronal cell.Naturally occurring variant

[0048] The term "naturally occurring variant" refers to variants of SNHG14 transcript downstream of SNORD109B gene or transcripts which originate from the same genetic loci as the target nucleic acid, but may differ for example, by virtue of degeneracy of the genetic code causing a multiplicity of codons in the long non-coding RNA. The oligonucleotide of the invention may therefore be designed to target the target nucleic acid and naturally occurring variants thereof.Modulation of expression

[0049] The term "modulation of expression" as used herein is to be understood as an overall term for an oligonucleotide's ability to alter the amount of UBE3A protein when compared to the amount of UBE3A before administration of the oligonucleotide. Alternatively modulation of expression may be determined by reference to a control experiment where the oligonucleotide of the invention is not administered. The modulation effected by the oligonucleotide is related to it's ability to reduce, remove, prevent, lessen, lower or terminate the suppression of the paternal UBE3A transcript, e.g. by degradation or removal of the non-coding SNHG14 transcript downstream of SNORD109B or by blockage or prevention of polymerase activity associated with the SNHG14 transcript downstream of SNORD109B. The modulation can also be viewed as the oligonucleotide's ability to restore, increase or enhance expression of paternal UBE3A, e.g. by removal or blockage of inhibitory mechanisms affected by the non-coding SNHG14 transcript downstream of SNORD109B.High affinity modified nucleosides

[0050] A high affinity modified nucleoside is a modified nucleotide which, when incorporated into the oligonucleotide enhances the affinity of the oligonucleotide for its complementary target, for example as measured by the melting temperature (T m< ). A high affinity modified nucleoside of the present invention preferably result in an increase in melting temperature between +0.5 to +12°C, more preferably between +1.5 to +10°C and most preferably between+3 to +8°C per modified nucleoside. Numerous high affinity modified nucleosides are known in the art and include for example, many 2' substituted nucleosides as well as locked nucleic acids (LNA) (see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213).Sugar modifications

[0051] The oligomer of the invention may comprise one or more nucleosides which have a modified sugar moiety, i.e. a modification of the sugar moiety when compared to the ribose sugar moiety found in DNA and RNA.

[0052] Numerous nucleosides with modification of the ribose sugar moiety have been made, primarily with the aim of improving certain properties of oligonucleotides, such as affinity and / or nuclease resistance.

[0053] Such modifications include those where the ribose ring structure is modified, e.g. by replacement with a hexose ring (HNA), or a bicyclic ring, which typically have a biradicle bridge between the C2 and C4 carbons on the ribose ring (LNA), or an unlinked ribose ring which typically lacks a bond between the C2 and C3 carbons (e.g. UNA). Other sugar modified nucleosides include, for example, bicyclohexose nucleic acids (WO2011 / 017521) or tricyclic nucleic acids (WO2013 / 154798). Modified nucleosides also include nucleosides where the sugar moiety is replaced with a non-sugar moiety, for example in the case of peptide nucleic acids (PNA), or morpholino nucleic acids.

[0054] Sugar modifications also include modifications made via altering the substituent groups on the ribose ring to groups other than hydrogen, or the 2'-OH group naturally found in DNA and RNA nucleosides. Substituents may, for example be introduced at the 2', 3', 4' or 5' positions. Nucleosides with modified sugar moieties also include 2' modified nucleosides, such as 2' substituted nucleosides. Indeed, much focus has been spent on developing 2' substituted nucleosides, and numerous 2' substituted nucleosides have been found to have beneficial properties when incorporated into oligonucleotides, such as enhanced nucleoside resistance and enhanced affinity.2' modified nucleosides.

[0055] A 2' sugar modified nucleoside is a nucleoside which has a substituent other than H or -OH at the 2' position (2' substituted nucleoside) or comprises a 2' linked biradicle, and includes 2' substituted nucleosides and LNA (2' - 4' biradicle bridged) nucleosides. For example, the 2' modified sugar may provide enhanced binding affinity and / or increased nuclease resistance to the oligonucleotide. Examples of 2' substituted modified nucleosides are 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2'-amino-DNA, 2'-Fluoro-RNA, and 2'-fluoro-ANA (F-ANA). For further examples, please see e.g. Freier & Altmann; Nucl. Acid Res., 1997, 25, 4429-4443 and Uhlmann; Curr. Opinion in Drug Development, 2000, 3(2), 293-213; and Deleavey and Damha, Chemistry and Biology 2012, 19, 937. Below are illustrations of some 2' substituted modified nucleosides. Locked Nucleic Acid Nucleosides (LNA).

[0056] LNA nucleosides are modified nucleosides which comprise a linker group (referred to as a biradicle or a bridge) between C2' and C4' of the ribose sugar ring of a nucleotide. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature.

[0057] As described herein, the modified nucleoside or the LNA nucleosides of the oligomer of the invention has a general structure of the formula I or II: wherein W is selected from -O-, -S-, -N(R a< )-, -C(R a< R b< )-, such as, in some embodiments -O-; B designates a nucleobase or modified nucleobase moiety; Z designates an internucleoside linkage to an adjacent nucleoside, or a 5'-terminal group; Z* designates an internucleoside linkage to an adjacent nucleoside, or a 3'-terminal group; X designates a group selected from the list consisting of -C(R a< R b< )-, -C(R a< )=C(R b< )-, - C(R a< )=N-, -O-, -Si(R a< ) 2 -, -S-, -SO 2 -, -N(R a< )-, and >C=Z

[0058] In some embodiments, X is selected from the group consisting of: -O-, -S-, NH-, NR a< R b< , -CH 2 -, CR a< R b< , -C(=CH 2 )-, and -C(=CR a< R b< )-

[0059] In some embodiments, X is -O- Y designates a group selected from the group consisting of -C(R a< R b< )-, -C(R a< )=C(R b< )-, - C(R a< )=N-, -O-, -Si(R a< ) 2 -, -S-, -SO 2 -, -N(R a< )-, and >C=Z

[0060] In some embodiments, Y is selected from the group consisting of: -CH 2 -, -C(R a< R b< )-, - CH 2 CH 2 -, -C(R a< R b< )-C(R a< R b< )-, -CH 2 CH 2 CH 2 -, -C(R a< R b< )C(R a< R b< )C(R a< R b< )-, -C(R a< )=C(R b< )-, and -C(R a< )=N-

[0061] In some embodiments, Y is selected from the group consisting of: -CH 2 -, -CHR a< -,-CHCH 3 -, CR a< R b< - or -X-Y- together designate a bivalent linker group (also referred to as a radicle) together designate a bivalent linker group consisting of 1, 2, 3 or 4 groups / atoms selected from the group consisting of -C(R a< R b< )-, -C(R a< )=C(R b< )-, -C(R a< )=N-, -O-, -Si(R a< ) 2 -, -S-, -SO 2 -, -N(R a< )-, and >C=Z,

[0062] In some embodiments, -X-Y- designates a biradicle selected from the groups consisting of: -X-CH 2 -, -X-CR a< R b< -, -X-CHR a-< , -X-C(HCH 3 ) -< , -O-Y-, -O-CH 2 -, -S-CH 2 -, -NH-CH 2 -, -O-CHCH 3 -, -CH 2 -O-CH 2 , -O-CH(CH 3 CH 3 )-, -O-CH 2 -CH 2 -, OCH 2 -CH 2 -CH 2 -,-O-CH 2 OCH 2 -, - O-NCH 2 -, -C(=CH 2 )-CH 2 -, -NR a< -CH 2 -, N-O-CH 2 , -S-CR a< R b< - and -S-CHR a< -.

[0063] In some embodiments -X-Y- designates -O-CH 2 - or -O-CH(CH 3 )-. wherein Z is selected from -O-, -S-, and -N(R a< )-, and R a< and, when present R b< , each is independently selected from hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, hydroxy, optionally substituted C 1-6 -alkoxy, C 2-6 -alkoxyalkyl, C 2-6 -alkenyloxy, carboxy, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)-amino-carbonyl, amino-C 1-6 -alkylaminocarbonyl, mono- and di(C 1-6 -alkyl)amino-C 1-6 -alkyl-aminocarbonyl, C 1-6 -alkylcarbonylamino, carbamido, C 1-6 -alkanoyloxy, sulphono, C 1-6 -alkylsulphonyloxy, nitro, azido, sulphanyl, C 1-6 -alkylthio, halogen, where aryl and heteroaryl may be optionally substituted and where two geminal substituents R a< and R b< together may designate optionally substituted methylene (=CH 2 ), wherein for all chiral centers, asymmetric groups may be found in either R or S orientation. wherein R 1< , R 2< , R 3< , R 5< and R 5*< are independently selected from the group consisting of: hydrogen, optionally substituted C 1-6 -alkyl, optionally substituted C 2-6 -alkenyl, optionally substituted C 2-6 -alkynyl, hydroxy, C 1-6 -alkoxy, C 2-6 -alkoxyalkyl, C 2-6 -alkenyloxy, carboxy, C 1-6 -alkoxycarbonyl, C 1-6 -alkylcarbonyl, formyl, aryl, aryloxy-carbonyl, aryloxy, arylcarbonyl, heteroaryl, heteroaryloxy-carbonyl, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C 1-6 -alkyl)amino, carbamoyl, mono- and di(C 1-6 -alkyl)-amino-carbonyl, amino-C 1-6 -alkylaminocarbonyl, mono- and di(C 1-6 -alkyl)amino-C 1-6 -alkyl-aminocarbonyl, C 1-6 -alkylcarbonylamino, carbamido, C 1-6 -alkanoyloxy, sulphono, C 1-6 -alkylsulphonyloxy, nitro, azido, sulphanyl, C 1-6 -alkylthio, halogen, where aryl and heteroaryl may be optionally substituted, and where two geminal substituents together may designate oxo, thioxo, imino, or optionally substituted methylene.

[0064] In some embodiments R 1< , R 2< , R 3< , R 5< and R 5*< are independently selected from C 1-6 alkyl, such as methyl, and hydrogen.

[0065] In some embodiments R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen.

[0066] In some embodiments R 1< , R 2< , R 3< , are all hydrogen, and either R 5< and R 5*< is also hydrogen and the other of R 5< and R 5*< is other than hydrogen, such as C 1-6 alkyl such as methyl.

[0067] In some embodiments, R a< is either hydrogen or methyl. In some embodiments, when present, R b< is either hydrogen or methyl.

[0068] In some embodiments, one or both of R a< and R b< is hydrogen

[0069] In some embodiments, one of R a< and R b< is hydrogen and the other is other than hydrogen In some embodiments, one of R a< and R b< is methyl and the other is hydrogen

[0070] In some embodiments, both of R a< and R b< are methyl.

[0071] In some embodiments, the biradicle -X-Y- is -O-CH 2 -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such LNA nucleosides are disclosed in WO99 / 014226, WO00 / 66604, WO98 / 039352 and WO2004 / 046160, and include what are commonly known as beta-D-oxy LNA and alpha-L-oxy LNA nucleosides.

[0072] In some embodiments, the biradicle -X-Y- is -S-CH 2 -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such thio LNA nucleosides are disclosed in WO99 / 014226 and WO2004 / 046160.

[0073] In some embodiments, the biradicle -X-Y- is -NH-CH 2 -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such amino LNA nucleosides are disclosed in WO99 / 014226 and WO2004 / 046160.

[0074] In some embodiments, the biradicle -X-Y- is -O-CH 2 -CH 2 - or -O-CH 2 -CH 2 - CH 2 -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such LNA nucleosides are disclosed in WO00 / 047599 and Morita et al, Bioorganic & Med.Chem. Lett. 12 73-76, and include what are commonly known as 2'-O-4'C-ethylene bridged nucleic acids (ENA).

[0075] In some embodiments, the biradicle -X-Y- is -O-CH 2 -, W is O, and all of R 1< , R 2< , R 3< , and one of R 5< and R 5*< are hydrogen, and the other of R 5< and R 5*< is other than hydrogen such as C 1-6 alkyl, such as methyl. Such 5' substituted LNA nucleosides are disclosed in WO2007 / 134181.

[0076] In some embodiments, the biradicle -X-Y- is -O-CR a< R b< -, wherein one or both of R a< and R b< are other than hydrogen, such as methyl, W is O, and all of R 1< , R 2< , R 3< , and one of R 5< and R 5*< are hydrogen, and the other of R 5< and R 5*< is other than hydrogen such as C 1-6 alkyl, such as methyl. Such bis modified LNA nucleosides are disclosed in WO2010 / 077578.

[0077] In some embodiments, the biradicle -X-Y- designate the bivalent linker group -O-CH(CH 2 OCH 3 )- (2' O-methoxyethyl bicyclic nucleic acid - Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle -X-Y- designate the bivalent linker group -O-CH(CH 2 CH 3 )- (2'O-ethyl bicyclic nucleic acid - Seth at al., 2010, J. Org. Chem. Vol 75(5) pp. 1569-81). In some embodiments, the biradicle -X-Y- is -O-CHR a< -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such 6' substituted LNA nucleosides are disclosed in WO10036698 and WO07090071.

[0078] In some embodiments, the biradicle -X-Y- is -O-CH(CH 2 OCH 3 )-, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such LNA nucleosides are also known as cyclic MOEs in the art (cMOE) and are disclosed in WO07090071.

[0079] In some embodiments, the biradicle -X-Y- designate the bivalent linker group -O-CH(CH 3 )-. - in either the R- or S- configuration. In some embodiments, the biradicle -X-Y- together designate the bivalent linker group -O-CH 2 -O-CH 2 - (Seth at al., 2010, J. Org. Chem). In some embodiments, the biradicle -X-Y- is -O-CH(CH 3 )-, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such 6' methyl LNA nucleosides are also known as cET nucleosides in the art, and may be either (S)cET or (R)cET stereoisomers, as disclosed in WO07090071 (beta-D) and WO2010 / 036698 (alpha-L).

[0080] In some embodiments, the biradicle -X-Y- is -O-CR a< R b< -, wherein in neither R a< or R b< is hydrogen, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. In some embodiments, R a< and R b< are both methyl. Such 6' di-substituted LNA nucleosides are disclosed in WO 2009006478.

[0081] In some embodiments, the biradicle -X-Y- is -S-CHR 3< -, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such 6' substituted thio LNA nucleosides are disclosed in. In some 6' substituted thio LNA embodiments R a< is methyl.

[0082] In some embodiments, the biradicle -X-Y- is -C(=CH2)-C(R a< R b< )-, such as -C(=CH 2 )-CH 2 -, or - C(=CH 2 )-CH(CH 3 )-W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. Such vinyl carbo LNA nucleosides are disclosed in WO08154401 and WO09067647.

[0083] In some embodiments the biradicle -X-Y- is -N(-OR a< )-, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. In some embodiments R a< is C 1-6 alkyl such as methyl. Such LNA nucleosides are also known as N substituted LNAs and are disclosed in WO2008 / 150729. In some embodiments, the biradicle -X-Y- together designate the bivalent linker group -O-NR a< -CH 3 -(Seth at al., 2010, J. Org. Chem). In some embodiments the biradicle -X-Y- is -N(R a< )-, W is O, and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. In some embodiments R a< is C 1-6 alkyl such as methyl.

[0084] In some embodiments, one or both of R 5< and R 5*< is hydrogen and, when substituted the other of R 5< and R 5*< is C 1-6 alkyl such as methyl. In such an embodiment, R 1< , R 2< , R 3< , may all be hydrogen, and the biradicle -X-Y- may be selected from -O-CH2- or -O-C(HCR a< )-, such as -O-C(HCH3)-.

[0085] In some embodiments, the biradicle is -CR a< R b< -O-CR a< R b< -, such as CH 2 -O-CH 2 -, W is O and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. In some embodiments R a< is C 1-6 alkyl such as methyl. Such LNA nucleosides are also known as conformationally restricted nucleotides (CRNs) and are disclosed in WO2013036868.

[0086] In some embodiments, the biradicle is -O-CR a< R b< -O-CR a< R b< -, such as O-CH 2 -O-CH 2 -, W is O and all of R 1< , R 2< , R 3< , R 5< and R 5*< are all hydrogen. In some embodiments R a< is C 1-6 alkyl such as methyl. Such LNA nucleosides are also known as COC nucleotides and are disclosed in Mitsuoka et al., Nucleic Acids Research 2009 37(4), 1225-1238.

[0087] It will be recognized than, unless specified, the LNA nucleosides may be in the beta-D or alpha-L stereoisoform.

[0088] Certain examples of LNA nucleosides are presented in Scheme 1.

[0089] As illustrated in the examples, in preferred embodiments of the invention the LNA nucleosides in the oligonucleotides are beta-D-oxy-LNA nucleosides.Nuclease mediated degradation

[0090] Nuclease mediated degradation refers to an oligonucleotide capable of mediating degradation of a complementary nucleotide sequence when forming a duplex with such a sequence.

[0091] In some embodiments, the oligonucleotide may function via nuclease mediated degradation of the target nucleic acid, where the oligonucleotides of the invention are capable of recruiting a nuclease, particularly and endonuclease, preferably endoribonuclease (RNase), such as RNase H. Examples of oligonucleotide designs which operate via nuclease mediated mechanisms are oligonucleotides which typically comprise a region of at least 5 or 6 DNA nucleosides and are flanked on one side or both sides by affinity enhancing nucleosides, for example gapmers, headmers and tailmers.RNase H Activity and Recruitment

[0092] The RNase H activity of an antisense oligonucleotide refers to its ability to recruit RNase H when in a duplex with a complementary RNA molecule. WO01 / 23613 provides in vitro methods for determining RNaseH activity, which may be used to determine the ability to recruit RNaseH. Typically an oligonucleotide is deemed capable of recruiting RNase H if it, when provided with a complementary target nucleic acid sequence, has an initial rate, as measured in pmol / l / min, of at least 10% or more than 20% of the of the initial rate determined when using a oligonucleotide having the same base sequence as the modified oligonucleotide being tested, but containing only DNA monomers, with phosphorothioate linkages between all monomers in the oligonucleotide, and using the methodology provided by Example 91 - 95 of WO01 / 23613.Gapmer

[0093] The term gapmer as used herein refers to an antisense oligonucleotide which comprises a region of RNase H recruiting oligonucleotides (gap) which is flanked 5' and 3' by one or more affinity enhancing modified nucleosides (flanks). Various gapmer designs are described herein. Headmers and tailmers are oligonucleotides capable of recruiting RNase H where one of the flanks is missing, i.e. only one of the ends of the oligonucleotide comprises affinity enhancing modified nucleosides. For headmers the 3' flank is missing (i.e. the 5' flanc comprise affinity enhancing modified nucleosides) and for tailmers the 5' flank is missing (i.e. the 3' flank comprises affinity enhancing modified nucleosides).LNA Gapmer

[0094] The term LNA gapmer is a gapmer oligonucleotide wherein at least one of the affinity enhancing modified nucleosides is an LNA nucleoside.Mixed Wing Gapmer

[0095] The term mixed wing gapmer refers to a LNA gapmer wherein the flank regions comprise at least one LNA nucleoside and at least one non-LNA modified nucleoside, such as at least one 2' substituted modified nucleoside, such as, for example, 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA (MOE), 2'-amino-DNA, 2'-Fluoro-RNA, and 2'-F-ANA nucleoside(s). In some embodiments the mixed wing gapmer has one flank which comprises LNA nucleosides (e.g. 5' or 3') and the other flank (3' or 5' respectfully) comprises 2' substituted modified nucleoside(s).Conjugate

[0096] The term conjugate as used herein refers to an oligonucleotide which is covalently linked to a non-nucleotide moiety (conjugate moiety or region C or third region).

[0097] Conjugation of the oligonucleotide of the invention to one or more non-nucleotide moieties may improve the pharmacology of the oligonucleotide, e.g. by affecting the activity, cellular distribution, cellular uptake or stability of the oligonucleotide. In some embodiments the conjugate moiety modify or enhance the pharmacokinetic properties of the oligonucleotide by improving cellular distribution, bioavailability, metabolism, excretion, permeability, and / or cellular uptake of the oligonucleotide. In particular the conjugate may target the oligonucleotide to a specific organ, tissue or cell type and thereby enhance the effectiveness of the oligonucleotide in that organ, tissue or cell type. A the same time the conjugate may serve to reduce activity of the oligonucleotide in non-target cell types, tissues or organs, e.g. off target activity or activity in non-target cell types, tissues or organs. WO 93 / 07883 and WO 2013 / 033230 provides suitable conjugate moieties. WO 2012 / 143379 provides a method of delivering a drug across the blood-brain-barrier by conjugation to an antibody fragment with affinity to the transferrin receptor.

[0098] Oligonucleotide conjugates and their synthesis has also been reported in comprehensive reviews by Manoharan in Antisense Drug Technology, Principles, Strategies, and Applications, S.T. Crooke, ed., Ch. 16, Marcel Dekker, Inc., 2001 and Manoharan, Antisense and Nucleic Acid Drug Development, 2002, 12, 103.

[0099] In an embodiment, the non-nucleotide moiety (conjugate moiety) is selected from the group consisting of carbohydrates, cell surface receptor ligands, drug substances, hormones, lipophilic substances, polymers, proteins, peptides, toxins (e.g. bacterial toxins), vitamins, viral proteins (e.g. capsids) or combinations thereof. In some embodiments the non-nucleotide moiety an antibody or antibody fragment, such as an antibody or antibody fragment that facilitates delivery across the blood-brain-barrier, in particular an antibody or antibody fragment targeting the transferrin receptor.Linkers

[0100] A linkage or linker is a connection between two atoms that links one chemical group or segment of interest to another chemical group or segment of interest via one or more covalent bonds. Conjugate moieties can be attached to the oligonucleotide directly or through a linking moiety (e.g. linker or tether). Linkers serve to covalently connect a third region, e.g. a conjugate moiety (Region C), to a first region, e.g. an oligonucleotide (region A).

[0101] In some embodiments of the invention the conjugate or oligonucleotide conjugate of the invention may optionally, comprise a linker region (second region or region B and / or region Y) which is positioned between the oligonucleotide (region A or first region) and the conjugate moiety (region C or third region).

[0102] Region B refers to biocleavable linkers comprising or consisting of a physiologically labile bond that is cleavable under conditions normally encountered or analogous to those encountered within a mammalian body. Conditions under which physiologically labile linkers undergo chemical transformation (e.g., cleavage) include chemical conditions such as pH, temperature, oxidative or reductive conditions or agents, and salt concentration found in or analogous to those encountered in mammalian cells. Mammalian intracellular conditions also include the presence of enzymatic activity normally present in a mammalian cell such as from proteolytic enzymes or hydrolytic enzymes or nucleases. In one embodiment the biocleavable linker is susceptible to S1 nuclease cleavage. In a preferred embodiment the nuclease susceptible linker comprises between 1 and 10 nucleosides, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleosides, more preferably between 2 and 6 nucleosides and most preferably between 2 and 4 linked nucleosides comprising at least two consecutive phosphodiester linkages, such as at least 3 or 4 or 5 consecutive phosphodiester linkages. Preferably the nucleosides are DNA or RNA. Phosphodiester containing biocleavable linkers are described in more detail in WO 2014 / 076195.

[0103] Region Y refers to linkers that are not necessarily biocleavable but primarily serve to covalently connect a conjugate moiety (region C or third region), to an oligonucleotide (region A or first region). The region Y linkers may comprise a chain structure or an oligomer of repeating units such as ethylene glycol, amino acid units or amino alkyl groups The oligonucleotide conjugates of the present invention can be constructed of the following regional elements A-C, A-B-C, A-BY-C, A-Y-B-C or A-Y-C. In some embodiments the linker (region Y) is an amino alkyl, such as a C2 - C36 amino alkyl group, including, for example C6 to C12 amino alkyl groups. In a preferred embodiment the linker (region Y) is a C6 amino alkyl group.Control

[0104] By the term "control" when used in relation to measurements of the effect of an oligonucleotide it is generally understood that the control is an untreated individual or target cell or a individual or target cell treated with a non-targeting oligonucleotide (mock). It may however also be an individual treated with the standard of care.Treatment

[0105] The term 'treatment' as used herein refers to both treatment of an existing disease (e.g. a disease or disorder as herein referred to), or prevention of a disease, i.e. prophylaxis. It will therefore be recognized that treatment as referred to herein may, in some embodiments, be prophylactic.DETAILED DESCRIPTION OF THE INVENTION The Target

[0106] An aspect of the invention is to modulate the level of pig, primate or human UBE3A protein expression, in particular to increase the expression of paternal UBE3A expression in neuronal cells, in particular in human neuronal cells. The human UBE3A protein exists in several isoforms which are listed under Uniprot nr. Q05086. Several mutations in the maternal UBE3A gene can results in Angelman syndrome.

[0107] The target nucleic acid for the oligonucleotide of the invention is RNA, in particular a long non-coding RNA. The long non-coding RNA which is targeted by the oligonucleotides of the present invention is human SNHG14 (also known as UBE3A-ATS with Ensembl entry number ENSG00000224078, version GRCh38.p2). In particular the target nucleic acid is the region downstream of SNORD109B corresponding to position 25278410 to 25419462 on chromosome 15 (SEQ ID NO: 1). In Rhesus monkey (Macaca mulatta) the UBE3A supressor is defined as region downstream of SNORD109A corresponding to position 4222848 to 4373084 (forward strand) on chromosome 7 using the Ensembl assembly MMUL 1.0 (SEQ ID NO: 2).

[0108] In some embodiments, the target nucleic acid is SEQ ID NO: 1, or naturally occurring variants thereof.

[0109] In certain embodiments the target nucleic acid correspond to regions which are conserved between human (SEQ ID NO: 1) and Rhesus monkey (SEQ ID NO: 2). In certain embodiments target nucleic acid correspond to regions which are conserved between human (SEQ ID NO:1), Rhesus monkey (SEQ ID NO: 2) and mouse (SEQ ID NO: 3).

[0110] In certain embodiments the target nucleic acid is the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 55319 to 141053 of SEQ ID NO: 1.

[0111] In certain embodiments the target nucleic acid is the region that is downstream of SNORD109B and upstream of the region that is antisense to the UBE3A pre-mRNA, this region corresponds to position 1 to 55319 of SEQ ID NO: 1.

[0112] In some embodiments, the target nucleic acid is present in a cell, such as a mammalian cell in particular a human cell in vitro or in vivo (the target cell). In certain embodiments the target cell is a neuron, preferably a human neuronal cell.

[0113] The target sequence may be a sub-sequence of the target nucleic acid. In some embodiments the oligonucleotide targets sub-sequence selected from the group consisting of the antisense region of exon 9, exon10, exon13, exon14, intron 14, exon 15, intron15 and exon 16 of UBE3A. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1. In some embodiments the oligonucleotide or contiguous nucleotide sequence hybridize or is complementary to a single stranded nucleic acid molecule selected from the group consisting of positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.

[0114] In some embodiments the target nucleic acid is a region corresponding to positions 9200-9250 of SEQ ID NO: 1.

[0115] In some embodiments the target nucleic acid is a region corresponding to positions 11505-11555 of SEQ ID NO: 1.

[0116] In some embodiments the target nucleic acid is a region corresponding to positions 15100-15150 of SEQ ID NO: 1.

[0117] In some embodiments the target nucleic acid is a region corresponding to positions 30590-30740 of SEQ ID NO: 1.

[0118] In some embodiments the target nucleic acid is a region corresponding to positions 46380-46430 of SEQ ID NO: 1.The Oligonucleotides of the Invention

[0119] The invention relates to oligonucleotides capable of modulating expression of paternal UBE3A, in particular induction or up-regulation of paternally expressed UBE3A in neuronal cells . The modulation is achieved by hybridizing to a target nucleic acid located on the long non-coding RNA SNHG14 transcript downstream of SNORD109B. In certain embodiments the oligonucleotide of the invention hybridizes to a sub-sequence of the target nucleic acid of SEQ ID NO: 1 with a ΔG° below -10 kcal, such as with a ΔG° between -10 to -60 kcal, such as -12 to -40, such as from -15 to -30 kcal or-16 to -27 kcal such as -18 to -25 kcal.

[0120] The oligonucleotide of the invention is an antisense oligonucleotide which targets the pig, rhesus monkey and / or human SNHG14 transcript downstream of SNORD109B.

[0121] In some embodiments the antisense oligonucleotide of the invention is capable of modulating the expression of the target by removing, interfering with or decreasing the suppressor of the target. Preferably, the oligonucleotide of the invention induces UBE3A expression in a cell, in particular paternal UBE3A expression in a neuron, by degradation or removal of the SNHG14 transcript downstream of SNORD109B. In some embodiments the oligonucleotide of the invention is capable of increasing the expression of UBE3A by least 20% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide. In additional embodiments the oligonucleotide of the invention is capable of decreasing the level of the SNHG14 transcript downstream of SNORD109B (in particular the part of the transcript that is antisense to the UBE3A pre-mRNA region) by at least 20% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% compared to the level of the SNHG14 transcript downstream of SNORD109B in a neuronal cell treated with saline or a non-targeting oligonucleotide, without reducing SNORD115 levels by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNORD115 in a cell treated with saline or a non-targeting oligonucleotide. SNRPN and SNORD116 transcripts are located upstream from the SNORD115 transcript consequently if the SNORD115 transcript is not reduced by the oligonucleotide it is highly likely that the SNRPN and SNORD116 transcripts are also not reduced. In a further embodiment SNRPN and SNORD116 transcripts levels are not reduced by more than 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25% or 30% compared to the level of SNRPN and SNORD116 in a cell treated with saline or a non-targeting oligonucleotide.

[0122] The target modulation is triggered by the hybridization between a contiguous nucleotide sequence of the oligonucleotide and the target nucleic acid. In some embodiments the oligonucleotide of the invention comprises mismatches between the oligonucleotide and the target nucleic acid. Despite mismatches hybridization to the target nucleic acid may still be sufficient to show a desired modulation of UBE3A expression. Reduced binding affinity resulting from mismatches may advantageously be compensated by increased number of nucleotides in the oligonucleotide and / or an increased number of modified nucleosides capable of increasing the binding affinity to the target, such as 2' modified nucleosides, including LNA, present within the oligonucleotide sequence.

[0123] Described herein is an antisense oligonucleotide which comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 95%, such as 98% such as 100% complementarity to position 25278410 to 25419462 on human chromosome 15.

[0124] As described herein, the oligonucleotide comprises a contiguous sequence which is at least 90% complementary, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, or 100% complementary with a region of the target nucleic acid shown as SEQ ID NO: 1, 2 or 3.

[0125] In a preferred embodiment the oligonucleotide of the invention, or contiguous nucleotide sequence thereof is fully complementary (100% complementary) to a region of the target nucleic acid shown as SEQ ID NO: 1, or in some embodiments may comprise one or two mismatches between the oligonucleotide and the target nucleic acid.

[0126] As described herein the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present in SEQ ID NO: 1 and SEQ ID NO: 2. In some embodiments the oligonucleotide sequence is 100% complementary to a corresponding target nucleic acid region present SEQ ID NO: 1, 2 and 3.

[0127] As described herein, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region A1 to A3649 in table 1. Table 1: Regions of SEQ ID NO 1 which may be targeted using oligonucleotide as described hereinReg. A Position in SEQ ID NO 1 Length Reg. A Position in SEQ ID NO 1 Length Reg. A Position in SEQ ID NO 1 Length from to from to from to 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[0128] In some embodiments, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as 100% complementarity, to a corresponding target nucleic acid region present in SEQ ID NO: 1, wherein the target nucleic acid region is selected from the group consisting of region B1 to B400 in table 2 Table 2: Regions of SEQ ID NO 1 which may be targeted using oligonucleotide of the inventionReg. Position in SEQ ID NO 1 Length Reg. Position in SEQ ID NO 1 Length Reg. Position in SEQ ID NO 1 Length To From To From To From 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

[0129] As described herein the oligonucleotide or contiguous nucleotide sequence is complementary to a region (or sub-sequence)(or sub-sequence) of the target nucleic acid, wherein the target nucleic acid region is selected from the group consisting of position 1589-10889, 46089-53989 and 60789-62489 of SEQ ID NO: 1.

[0130] As described herein the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 55319 to 141053 of SEQ ID NO: 1.

[0131] As described herein the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90%, such as 100% complementary to a target nucleic acid sequence of position 1 to 55318 of SEQ ID NO: 1.

[0132] As described herein, the oligonucleotide comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions : 55319-76274, 77483-77573, 92157-93403 and 97056-97354 of SEQ ID NO: 1.

[0133] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid selected from the group corresponding to positions: 60821-60849, 77567-77583, 92323-92339 and 97156-97172 of SEQ ID NO: 1.

[0134] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5218-5240 of SEQ ID NO: 1.

[0135] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 5782-5803 of SEQ ID NO: 1.

[0136] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 8113-8139 of SEQ ID NO: 1.

[0137] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 9200-9250 of SEQ ID NO: 1.

[0138] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 11505-11555 of SEQ ID NO: 1.

[0139] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions: 13223-13242 of SEQ ID NO: 1.

[0140] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15100-15150 of SEQ ID NO: 1.

[0141] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 15113-15180 of SEQ ID NO: 1.

[0142] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 29635-29705 of SEQ ID NO: 1.

[0143] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 30590-30740 of SEQ ID NO: 1.

[0144] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid corresponding to positions 39800-39855 of SEQ ID NO: 1.

[0145] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 44435-44460 of SEQ ID NO: 1.

[0146] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 45245-45270 of SEQ ID NO: 1.

[0147] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 46380-46430 of SEQ ID NO: 1.

[0148] As described herein the oligonucleotide a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary to a sub-sequence of the target nucleic acid to positions 68915-68940 of SEQ ID NO: 1.

[0149] As described herein, the oligonucleotide comprises or consists of 8 to 35 nucleotides in length, such as from 10 to 30, such as 11 to 22, such as from 12 to 18, such as from 13 to 17 or 14 to 16 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 15 to20 nucleotides in length.

[0150] As described herein, the oligonucleotide or contiguous nucleotide sequence thereof comprises or consists of 22 or less nucleotides, such as 20 or less nucleotides, such as 18 or less nucleotides, such as 14, 15, 16 or 17 nucleotides. It is to be understood that any range given herein includes the range endpoints. Accordingly, if an oligonucleotide is said to include from 10 to 30 nucleotides, both 10 and 30 nucleotides are included.

[0151] As described herein, the contiguous nucleotide sequence comprises or consists of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 contiguous nucleotides in length. In a preferred embodiment, the oligonucleotide comprises or consists of 16, 17, 18 or 19 nucleotides in length.

[0152] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 150 (see motif sequences listed in table 3 in the Examples section).

[0153] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 818 (see motif sequences listed in table 3 in the Examples section).

[0154] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 4 to 678 (see motif sequences listed in table 3 in the Examples section).

[0155] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 166, 167, 167 or 169 (see motif sequences listed in table 3 in the Examples section).

[0156] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 570, 571 ,572, 679, 680, 681, 682 and 683 (see motif sequences listed in table 3 in the Examples section).

[0157] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 34, 186, 187, 188, 573, 574, 575, 576, 572, 684, 685, 686, 687, 688, 689, 690, 691, 692, 963, 964, 965 and 696 (see motif sequences listed in table 3 in the Examples section).

[0158] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 35, 199, 200, 201, 202, 203, 204, 205, 206, 207, 209 and 210 or SEQ ID NO: 582, 583 and 584 (see motif sequences listed in table 3 in the Examples section).

[0159] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 221, 222, 223, 224, 225, 585, 586, 587, 588, 589, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717 and 718 (see motif sequences listed in table 3 in the Examples section).

[0160] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 236, 237, 238, 239, 240 and 590.

[0161] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 241, 591 and 719 (see motif sequences listed in table 3 in the Examples section).

[0162] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 46, 47,48, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304,305, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626,627, 628, 629, 630, 631, 632, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 800, 800, 800, 800, 801, 801, 802, 803, 804, 805, 806 and 807 (see motif sequences listed in table 3 in the Examples section).

[0163] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 331, 332, 638, 639, 640, 808, 809, 810 ,811 ,812, 813, 814 and 815 (see motif sequences listed in table 3 in the Examples section).

[0164] As described herein, the antisense oligonucleotide or contiguous nucleotide sequence comprises or consists of of 10 to 30 nucleotides in length with at least 90% identity, preferably 100% identity to a sequence selected from the group consisting of SEQ ID NO: 409, 410, 411, 642, 643, 644, 645, 646, 816, 818 and 818 (see motif sequences listed in table 3 in the Examples section).

[0165] It is understood that the contiguous nucleobase sequences (motif sequence) can be modified to for example increase nuclease resistance and / or binding affinity to the target nucleic acid. Modifications are described in the definitions and in the "Oligonucleotide design" section. Table 3 lists preferred designs of each motif sequence.Oligonucleotide design

[0166] Oligonucleotide design refers to the pattern of nucleoside sugar modifications in the oligonucleotide sequence. The oligonucleotides as described herein comprise sugar-modified nucleosides and may also comprise DNA or RNA nucleosides. As described herein, the oligonucleotide comprises sugar-modified nucleosides and DNA nucleosides. Incorporation of modified nucleosides into the oligonucleotide of the invention may enhance the affinity of the oligonucleotide for the target nucleic acid. In that case, the modified nucleosides can be referred to as affinity enhancing modified nucleotides.

[0167] As described herein, the oligonucleotide comprises at least 1 modified nucleoside, such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 modified nucleosides. As described herein the oligonucleotide comprises from 1 to 10 modified nucleosides, such as from 2 to 9 modified nucleosides, such as from 3 to 8 modified nucleosides, such as from 4 to 7 modified nucleosides, such as 6 or 7 modified nucleosides. As described herein, at least 1 of the modified nucleosides is a locked nucleic acid (LNA), such as at least 2, such as at least 3, at least 4, at least 5, at least 6, at least 7, or at least 8 of the modified nucleosides are LNA. In a still further embodiment all the modified nucleosides are LNA.

[0168] As described herein, the oligonucleotide of the invention may comprise modifications, which are independently selected from these three types of modifications (modified sugar, modified nucleobase and modified internucleoside linkage) or a combination thereof. Preferably the oligonucleotide comprises one or more sugar modified nucleosides, such as 2' sugar modified nucleosides. Preferably the oligonucleotide of the invention comprise the one or more 2' sugar modified nucleoside independently selected from the group consisting of 2'-O-alkyl-RNA, 2'-O-methyl-RNA, 2'-alkoxy-RNA, 2'-O-methoxyethyl-RNA, 2'-amino-DNA, 2'-fluoro-DNA, arabino nucleic acid (ANA), 2'-fluoro-ANA and LNA nucleosides. Even more preferably the the one or more modified nucleoside is LNA.

[0169] As described herein the oligonucleotide comprises at least one modified internucleoside linkage. In a preferred embodiment the the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate or boranophosphate internucleoside linkages.

[0170] As described herein, the oligonucleotide of the invention comprise at least one modified nucleoside which is a 2'-MOE-RNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2'-MOE-RNA nucleoside units. As described herein, at least one of said modified nucleoside is 2'-fluoro DNA, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 2'-fluoro-DNA nucleoside units.

[0171] As described herein, the oligonucleotide of the invention comprises at least one LNA unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such as from 2 to 6 LNA units, such as from 3 to 7 LNA units, 4 to 8 LNA units or 3, 4, 5, 6 or 7 LNA units. As described herein, all the modified nucleosides are LNA nucleosides. As described herein, the oligonucleotide may comprise both beta-D-oxy-LNA, and one or more of the following LNA units: thio-LNA, amino-LNA, oxy-LNA, and / or ENA in either the beta-D or alpha-L configurations or combinations thereof. In a further embodiment, all LNA cytosine units are 5-methyl-cytosine. As described herein the oligonucleotide or contiguous nucleotide sequence has at least 1 LNA unit at the 5' end and at least 2 LNA units at the 3' end of the nucleotide sequence.

[0172] The oligonucleotide as described herein comprises at least one LNA unit and at least one 2' substituted modified nucleoside.

[0173] As described herein, the oligonucleotide comprise both 2' sugar modified nucleosides and DNA units. Preferably the oligonucleotide comprise both LNA and DNA units. Preferably, the combined total of LNA and DNA units is 8-30, such as 10 - 25, preferably 12-22, such as 12 - 18, even more preferably 11-16. As described herein, the nucleotide sequence of the oligonucleotide, such as the contiguous nucleotide sequence consists of at least one or two LNA units and the remaining nucleotide units are DNA units. As described herein the oligonucleotide comprises only LNA nucleosides and naturally occurring nucleosides (such as RNA or DNA, most preferably DNA nucleosides), optionally with modified internucleoside linkages such as phosphorothioate.

[0174] In an embodiment of the invention the oligonucleotide of the invention is capable of recruiting RNase H.Gapmer design

[0175] In a preferred embodiment the oligonucleotide of the invention has a gapmer design or structure also referred herein merely as "Gapmer". In a gapmer structure the oligonucleotide comprises at least three distinct structural regions a 5'-flank, a gap and a 3'-flank, F-G-F' in '5 -> 3' orientation. In this design, flanking regions F and F' (also termed wing regions) comprise a contiguous stretch of modified nucleosides, which are complementary to the UBE3A target nucleic acid, while the gap region, G, comprises a contiguous stretch of nucleotides which are capable of recruiting a nuclease, preferably an endonuclease such as RNase, for example RNase H, when the oligonucleotide is in duplex with the target nucleic acid. Nucleosides which are capable of recruiting a nuclease, in particular RNase H, can be selected from the group consisting of DNA, alpha-L-oxy-LNA, 2'-Flouro-ANA and UNA. Regions F and F', flanking the 5' and 3' ends of region G, preferably comprise non-nuclease recruiting nucleosides (nucleosides with a 3' endo structure), more preferably one or more affinity enhancing modified nucleosides. As described herein, the 3' flank comprises at least one LNA nucleoside, preferably at least 2 LNA nucleosides. As described herein, the 5' flank comprises at least one LNA nucleoside. As described herein both the 5' and 3' flanking regions comprise a LNA nucleoside. As described herein all the nucleosides in the flanking regions are LNA nucleosides. As described herein, the flanking regions may comprise both LNA nucleosides and other nucleosides (mixed flanks), such as DNA nucleosides and / or non-LNA modified nucleosides, such as 2' substituted nucleosides. In this case the gap is defined as a contiguous sequence of at least 5 RNase H recruiting nucleosides (nucleosides with a 2' endo structure, preferably DNA) flanked at the 5' and 3' end by an affinity enhancing modified nucleoside, preferably LNA, such as beta-D-oxy-LNA. Consequently, the nucleosides of the 5' flanking region and the 3' flanking region which are adjacent to the gap region are modified nucleosides, preferably non-nuclease recruiting nucleosides. In oligonucleotides with mixed flanks where the flanks comprise DNA the 5' and 3' nucleosides are modified nucleosides.Region F

[0176] Region F (5' flank or 5' wing) attached to the '5 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. As decribed herein F comprises or consists of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleosides, such as from 2 to 5 modified nucleosides, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. As decribed herein further additional nucleosides may be attached to the '5 end of region F, representing a region D preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D can take the function of a biocleavable (B) linker described in the definition of "Linkers ".

[0177] As decribed herein, the modified nucleosides in region F have a 3' endo structure.

[0178] As decribed herein, one or more of the modified nucleosides in region F are 2' modified nucleosides.

[0179] As decribed herein one or more of the 2' modified nucleosides in region F are selected from 2'-O-alkyl-RNA units, 2'-O-methyl-RNA, 2'-amino-DNA units, 2'-fluoro-DNA units, 2'-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2'-fluoro-ANA units.

[0180] As decribed herein all the modified nucleosides in region F are LNA nucleosides. In a further embodiment the LNA nucleosides in region F are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET, and / or ENA, in either the beta-D or alpha-L configurations or combinations thereof. As decribed herein region F has at least 1 beta-D-oxy LNA unit, at the 5' end of the contiguous sequence.Region G

[0181] Region G (gap region) preferably comprise, contain or consist of at least 4, such as at least 5, such as at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15 or at least 16 consecutive nucleosides capable of recruiting the aforementioned nuclease, in particular RNaseH. As decribed herein region G comprise, contain or consist of from 5 to 12, or from 6 to 10 or from 7 to 9, such as 8 consecutive nucleotide units capable of recruiting aforementioned nuclease.

[0182] The nucleoside units in region G, which are capable of recruiting nuclease are as decribed herein selected from the group consisting of DNA, alpha-L-LNA, C4' alkylated DNA (as described in PCT / EP2009 / 050349 and Vester et al., Bioorg. Med. Chem. Lett. 18 (2008) 2296 - 2300), arabinose derived nucleosides like ANA and 2'F-ANA (Mangos et al. 2003 J. AM. CHEM. SOC. 125, 654-661), UNA (unlocked nucleic acid) (as described in Fluiter et al., Mol. Biosyst., 2009, 10, 1039). UNA is unlocked nucleic acid, typically where the bond between C2 and C3 of the ribose has been removed, forming an unlocked "sugar" residue.

[0183] As decribed herein at least one nucleoside unit in region G is a DNA nucleoside unit, such as from 1 to 16 DNA units, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 DNA units, preferably from 2 to 13 DNA units, such as from 4 to 12 DNA units, more preferably from 5 to 11, or from 10 to 16, 11 to 15 or 12 to 14 DNA units. In some embodiments, region G consists of 100% DNA units. As decribed herein, G consists of , most preferably 10, 11, 12, 13, 14 or 15 DNA units.

[0184] As decribed herein the region G may consist of a mixture of DNA and other nucleosides capable of mediating RNase H cleavage. Region G may consist of at least 50% DNA, more preferably 60 %, 70% or 80 % DNA, and even more preferred 90% or 95% DNA.

[0185] As decribed herein at least one nucleoside unit in region G is an alpha-L-LNA nucleoside unit, such as at least one alpha-L-LNA unit, such as 2, 3, 4, 5, 6, 7, 8 or 9 alpha-L-LNA units. As decribed herein, region G comprises the least one alpha-L-LNA is alpha-L-oxy-LNA unit. As decribed herein region G comprises a combination of DNA and alpha-L-LNA nucleoside units.

[0186] As decribed herein the size of the contiguous sequence in region G may be longer, such as 15, 16, 17, 18, 19 or 20 nucleoside units.

[0187] As decribed herein, nucleosides in region G have a 2' endo structure.Region F'

[0188] Region F' (3' flank or 3' wing) attached to the '3 end of region G comprises, contains or consists of at least one modified nucleoside such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 modified nucleosides. As decribed herein region F' comprise or consist of from 1 to 7 modified nucleosides, such as from 2 to 6 modified nucleoside, such as from 2 to 4 modified nucleosides, such as from 1 to 3 modified nucleosides, such as 1, 2, 3 or 4 modified nucleosides. In a further embodiment further additional nucleosides attached to the '3 end of region F', representing a region D', preferably comprising 1, 2 or 3 nucleoside units, such as DNA nucleosides. Region D' can take the function of a biocleavable (B) linker described, in the section "Linkers".

[0189] As decribed herein, the modified nucleosides in region F' have a 3' endo structure.

[0190] As decribed herein, modified nucleosides in region F' is LNA.

[0191] As decribed herein modified nucleosides in region F' are selected from 2'-O-alkyl-RNA units, 2'-O-methyl-RNA, 2'-amino-DNA units, 2'-fluoro-DNA units, 2'-alkoxy-RNA, MOE units, LNA units, arabino nucleic acid (ANA) units and 2'-fluoro-ANA units.

[0192] As decribed herein all the modified nucleosides in region F' are LNA nucleosides. As decribed herein the LNA nucleosides in region F' are independently selected from the group consisting of oxy-LNA, thio-LNA, amino-LNA, cET and / or ENA, in either the beta-D or alpha-L configurations or combinations thereof. As decribed herein region F' has at least 2 beta-D-oxy LNA unit, at the 3' end of the contiguous sequence.Region D and D'

[0193] Region D and D' can be attached to the 5' end of region F or the 3' end of region F', respectively.

[0194] Region D or D' may independently comprise 1, 2, 3, 4 or 5 additional nucleotides, which may be complementary or non-complementary to the target nucleic acid. In this respect the oligonucleotide of the invention, may in some embodiments comprise a contiguous nucleotide sequence capable of modulating the target which is flanked at the 5' and / or 3' end by additional nucleotides. Such additional nucleotides may serve as a nuclease susceptible biocleavable linker (see definition of linkers). In some embodiments the additional 5' and / or 3' end nucleotides are linked with phosphodiester linkages, and may be DNA or RNA. In another embodiment, the additional 5' and / or 3' end nucleotides are modified nucleotides which may for example be included to enhance nuclease stability or for ease of synthesis. In an embodiment of the oligonucleotide of the invention, comprises a region D and / or D' in addition to the contiguous nucleotide sequence.

[0195] The gapmer oligonucleotide of the present invention can be represented by the following formulae: F-G-F'; in particular F 1-7 -G 4-12 -F' 1-7 D-F-G-F', in particular D 1-3 -F 1-7 G 4-12 -F' 1-7 F-G-F'-D', in particular F 1-7 G 4-12 -F' 1-7 D' 1-3 D-F-G-F'-D', in particular D 1-3 -F 1-7 G 4-12 -F' 1-7 D' 1-3

[0196] The preferred number and types of nucleosides in regions F, G and F', D and D' have been described above. The design of the individual oligonucleotide may also have profound impact on the properties of the oligonucleotide in its use for modulating expression of UBE3A.

[0197] As decribed herein the oligonucleotide is a gapmer consisting of 14, 15, 16, 17, 18, 19 or 20 nucleotides in length, wherein each of regions F and F' independently consists of 2, 3 or 4 modified nucleoside units complementary to a part of the human SNHG14 long non-coding RNA which is antisense to the UBE3A pre-mRNA (the target nucleic acid) and region G consists of 10, 11, 12 ,13, 14 or 15 nucleoside units, capable of recruiting nuclease when in duplex with the target nucleic acid.

[0198] As decribed herein, the oligonucleotide is a gapmer wherein each of regions F and F' independently consists of 2, 3, 4 or 5 modified nucleoside units, such as nucleoside units containing a 2'-O-methoxyethyl-ribose sugar (2'-MOE) or nucleoside units containing a 2'-fluoro-deoxyribose sugar and / or LNA units, and region G consists of 9, 10, 11, 12,13, 14 or 15 nucleoside units, such as DNA units or other nuclease recruiting nucleosides such as alpha-L-LNA or a mixture of DNA and nuclease recruiting nucleosides.

[0199] As decribed herein, the oligonucleotide is a gapmer wherein each of regions F and F' region consists of two LNA units each, and region G consists of 10, 11, 12, 13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 2-10-2, 2-11-2, 2-12-2, 2-13-2, 2-14-2 and 2-15-2.

[0200] As decribed herein, the oligonucleotide is a gapmer wherein each of regions F and F' independently consists of three LNA units, and region G consists of 10, 11, 12,13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 3-10-3, 3-11-3, 3-12-3, 3-13-3, 3-14-3 and 3-15-3.

[0201] As decribed herein, the oligonucleotide is a gapmer wherein each of regions F and F' consists of four LNA units each, and region G consists of 10, 11, 12,13, 14 or 15 nucleoside units, preferably DNA units. Specific gapmer designs of this nature include 4-10-4, 4-11-4, 4-12-4, 4-13-4, 4-14-4 and 4-15-4.

[0202] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 10 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-10-1, 2-10-1, 1-10-2, 1-10-3, 3-10-1, 1-10-4, 4-10-1, 2-10-2, 2-10-3, 3-10-2, 2-10-4, 4-10-2, 3-10-3, 3-10-4, 4-10-3 and 4-10-4 gapmers.

[0203] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 11 nucleosides and independently 1 to 4 modified nucleosides in the wings including, 1-11-1, 2-11-1, 1-11-2, 1-11-3, 3-11-1, 1-11-4, 4-11-1, 2-11-2, 2-11-3, 3-11-2, 2-11-4, 4-11-2, 3-11-3, 3-11-4, 4-11-3 and 4-11-4 gapmers.

[0204] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 12 nucleosides including, 1-12-1, 2-12-1, 1-12-2, 1-12-3, 3-12-1, 1-12-4, 4-12-1, 2-12-2, 2-12-3, 3-12-2, 2-12-4, 4-12-2, 3-12-3, 3-12-4, 4-12-3 and 4-12-4 gapmers.

[0205] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 13 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-13-1, 1-13-2, 1-13-3, 3-13-1, 1-13-4, 4-13-1,2-13-1, 2-13-2, 2-13-3, 3-13-2, 2-13-4, , 4-13-2, 3-13-3, 3-13-4, 4-13-3, and 4-13-4 gapmers.

[0206] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 14 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-14-1, 1-14-2, 2-14-1, 1-14-3, 3-14-1, 1-14-4, 4-14-1, 2-14-2, 2-14-3, 3-14-2 2-14-4, 4-14-2, 3-14-3, 3-14-4 and 4-14-3 gapmers.

[0207] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 15 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-15-1, 1-15-2, 2-15-1, 1-15-3, 3-15-1, 1-15-4, 4-15-1, 2-15-2, 2-15-3, 3-15-2 2-15-4, 4-15-2, 3-15-3, 3-15-4 and 4-15-3 gapmers.

[0208] Specific gapmer designs of this nature include F-G-F' designs selected from a group consisting of a gap with 16 nucleosides and independently 1 to 4 modified nucleosides in the wings including 1-16-1, 1-16-2, 2-16-1, 1-15-3, 3-16-1, 1-16-4, 4-16-1, 2-16-2, 2-16-3, 3-16-2 2-16-4, 4-16-2, 3-16-3, 3-16-4 and 4-16-3 gapmers.

[0209] As decribed herein the F-G-F' design is selected from 2-10-4, 3-10-3 and 4-10-2.

[0210] As decribed herein the F-G-F' design is selected from 2-11-4, 3-11-2, 3-11-3 and 4-11-2.

[0211] As decribed herein the F-G-F' design is selected from 2-12-2, 2-12-3, 2-12-4, 3-12-2, 3-12-3, and 4-12-2.

[0212] As decribed herein the F-G-F' design is selected from 2-13-2, 2-13-3, 2-13-4, 3-13-3 and 4-13-2.

[0213] As decribed herein the F-G-F' design is selected from 2-14-2, 2-14-4, 3-14-3 and 4-14-2.

[0214] As decribed herein the F-G-F' design is selected from 2-15-2 and 2-16-2.

[0215] As decribed herein the F-G-F' design is selected from the designs indicated in table 3.

[0216] In all instances the F-G-F' design may further include region D and / or D', which may have 1, 2 or 3 nucleoside units, such as DNA units. Preferably, the nucleosides in region F and F' are modified nucleosides, while nucleotides in region G are preferably unmodified nucleosides.

[0217] In each design, the preferred modified nucleoside is LNA.

[0218] As decribed herein all the internucleoside linkages in the gap in a gapmer are phosphorothioate and / or boranophosphate linkages. As decribed herein all the internucleoside linkages in the flanks (F and F' region) in a gapmer are phosphorothioate and / or boranophosphate linkages. As decribed herein all the internucleoside linkages in the D and D' region in a gapmer are phosphodiester linkages.

[0219] For specific gapmers as disclosed herein, when the cytosine (C) residues are annotated as 5-methyl-cytosine, as decribed herein, one or more of the C's present in the oligonucleotide may be unmodified C residues.

[0220] Further gapmer designs are disclosed in WO2004 / 046160, and WO2007 / 146511.

[0221] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds in table 3.

[0222] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 150_2.

[0223] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 678_1.

[0224] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 4_1 to 818_1 (see oligonucleotide sequences listed in table 3 in the Examples section).

[0225] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 155_1 or 165_1.

[0226] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 169_52, 169_50 or 169_56.

[0227] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 172_1, 272_1, 572_7, 572_6 or 572_5.

[0228] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 175_1.

[0229] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 178_1.

[0230] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 573_8, 186_1 or 187_1.

[0231] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 186_1.

[0232] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 200_1, 204_1, 206_1, 35_2 or 209_1.

[0233] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 585_1, 585_8, 586_9, 586_5, 586_8, 586_4 or 586_6.

[0234] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 233_1.

[0235] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 237_8 or 590_13.

[0236] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 220_1.

[0237] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 591_1, 592_2, 592_4 or 241_9.

[0238] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 597_4, 598_4, 39_1 or 602_1.

[0239] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 39_1.

[0240] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 611_7.

[0241] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 271_1 or 278_1.

[0242] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 616_4, 621_2, 621_1, 622_3, 622_5, 622_4, 624_3, 624_5, 287_1, 625_6, 626_7, 626_8, 626_9, 48_1, 631_6, 631_1, 303_1, 304_6 or 304_10.

[0243] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 636_8.

[0244] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 638_8, 639_5, 331_1 or 640_4.

[0245] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 359_1, 361_1, 361_5, 362_1 or 641_5.

[0246] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 378_1, 379_1, 399_1.

[0247] As decribed herein, the oligonucleotide is selected from the group of oligonucleotide compounds with CMP-ID-NO: 403_1, 405_1, 642_12, 642_13, 644_3 or 646_16.

[0248] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 85_1 or 425_5.

[0249] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 116_1.

[0250] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 123_1 or 124_1.

[0251] As decribed herein, the oligonucleotide is an oligonucleotide compound with CMP-ID-NO: 126_2.Method of manufacture

[0252] Described herein are methods for manufacturing the oligonucleotides of the invention comprising reacting nucleotide units and thereby forming covalently linked contiguous nucleotide units comprised in the oligonucleotide. Preferably, the method uses phophoramidite chemistry (see for example Caruthers et al, 1987, Methods in Enzymology vol. 154, pages 287-313). As decribed herein the method further comprises reacting the contiguous nucleotide sequence with a conjugating moiety (ligand). As decribed herein a method is provided for manufacturing the composition of the invention, comprising mixing the oligonucleotide or conjugated oligonucleotide of the invention with a pharmaceutically acceptable diluent, solvent, carrier, salt and / or adjuvant.Pharmaceutical Composition

[0253] As decribed herein, the invention provides pharmaceutical compositions comprising any of the aforementioned oligonucleotides and / or oligonucleotide conjugates and a pharmaceutically acceptable diluent, carrier, salt and / or adjuvant. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS) and pharmaceutically acceptable salts include sodium and potassium salts.

[0254] WO 2007 / 031091 provides suitable and preferred examples of pharmaceutically acceptable diluents, carriers and adjuvants. Suitable dosages, formulations, administration routes, compositions, dosage forms, combinations with other therapeutic agents, pro-drug formulations are also provided in WO2007 / 031091.

[0255] Oligonucleotides or oligonucleotide conjugates of the invention may be mixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including route of administration, extent of disease, or dose to be administered.

[0256] In some embodiments, the oligonucleotide or oligonucleotide conjugate of the invention is a prodrug. In particular with respect to oligonucleotide conjugates the conjugate moiety is cleaved of the oligonucleotide once the prodrug is delivered to the site of action, e.g. the target cell.Applications

[0257] The oligonucleotides of the invention may be utilized as research reagents for, for example, therapeutics and prophylaxis.

[0258] In research, such oligonucleotides may be used to specifically modulate the synthesis of UBE3A protein in cells (e.g. in vitro cell cultures) and experimental animals thereby facilitating functional analysis of the target or an appraisal of its usefulness as a target for therapeutic intervention. The target modulation is achieved by degrading or inhibiting a modulator of the gene or mRNA producing the protein.

[0259] For therapeutics, an animal or a human, suspected of having a disease or disorder, which can be treated by modulating the expression of UBE3A.

[0260] Described herein are methods for treating or preventing a disease, comprising administering a therapeutically or prophylactically effective amount of an oligonucleotide, an oligonucleotide conjugate or a pharmaceutical composition of the invention to a subject suffering from or susceptible to the disease.

[0261] The invention also relates to an oligonucleotide, a composition or a conjugate as defined herein for use as a medicament.

[0262] The oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition according to the invention is typically administered in an effective amount.

[0263] Described herein is the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament for the treatment of a disorder as referred to herein, or for a method of the treatment of as a disorder as referred to herein.

[0264] The disease or disorder, as referred to herein, is associated with expression of UBE3A. As described herein the disease or disorder may be associated with a mutation in the maternal UBE3A gene. In some embodiments, the target nucleic acid is a regulator of the paternal UBE3A gene.

[0265] The methods described herein are preferably employed for treatment or prophylaxis against diseases caused by abnormal levels and / or activity of UBE3A. The disease may in particular be caused by reduced levels and / or activity of UBE3A protein.

[0266] Described herein is use of an oligonucleotide, oligonucleotide conjugate or a pharmaceutical composition as defined herein for the manufacture of a medicament for the treatment of abnormal levels and / or activity of UBE3A, in particular low levels and / or activity of UBE3A.

[0267] In one embodiment, the invention relates to oligonucleotides, oligonucleotide conjugates or pharmaceutical compositions for use in the treatment of Angelman symdrome.Administration

[0268] The oligonucleotides or pharmaceutical compositions of the present invention may be administered topical (such as, to the skin, inhalation, ophthalmic or otic) or enteral (such as, orally or through the gastrointestinal tract) or parenteral (such as, intravenous, subcutaneous, intra-muscular, intracerebral, intracerebroventricular or intrathecal).

[0269] In a preferred embodiment the oligonucleotide or pharmaceutical compositions of the present invention are administered by a parenteral route including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, intrathecal or intracranial, e.g., intracerebral or intraventricular, administration. In one embodiment the active oligonucleotide or oligonucleotide conjugate is administered intracerebral or intracerebroventricular. In another embodiment the active oligonucleotide or oligonucleotide conjugate is administered intrathecal.

[0270] Described herein is the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intrathecal administration.

[0271] Described herein is the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebral or intraventricular administration.

[0272] Described herein is the use of the oligonucleotide or oligonucleotide conjugate of the invention as described for the manufacture of a medicament wherein the medicament is in a dosage form for intracerebroventricular administration.Combination therapies

[0273] In some embodiments the oligonucleotide, oligonucleotide conjugate or pharmaceutical composition of the invention is for use in a combination treatment with another therapeutic agent. The therapeutic agent can for example be anticonvulsant medication.EXAMPLES Materials and methods

[0274] Table 3: List of oligonucleotides or contiguous nucleobase sequences complementary to SEQ ID NO: 1 (motif sequences indicated by SEQ ID NO), oligonucleotide designs made from these, as well as specific oligonucleotide compounds (indicated by CMP ID NO) designed based on the motif sequence.Seq ID NOMotifDesignCompoundCMP ID NOΔG°Start SEQ ID NO 14AACTTCATCAATATTTCCC3-13-3AACttcatcaatatttCCC4_1-23,3616774AACTTCATCAATATTTCCC2-15-2AActtcatcaatatttcCC4_2-19,6016775ACTTCATCAATATTTCCC3-12-3ACTtcatcaatatttCCC5_1-23,8016775ACTTCATCAATATTTCCC2-14-2ACttcatcaatatttcCC5_2-20,2416776CAACTTCATCAATATTTCCC2-14-4CAacttcatcaatattTCCC6_1-25,6416776CAACTTCATCAATATTTCCC2-16-2CAacttcatcaatatttcCC6_2-22,2816777CAACTTCATCAATATTTCC4-13-2CAACttcatcaatatttCC7_1-21,4716787CAACTTCATCAATATTTCC2-15-2CAacttcatcaatatttCC7_2-19,4616788CCAACTTCATCAATATTTCC3-14-3CCAacttcatcaatattTCC8_1-25,6416789CCCAACTTCATCAATATTTC4-14-2CCCAacttcatcaatattTC9_1-25,64167910ACCCAACTTCATCAATATTT2-16-2ACccaacttcatcaatatTT10_1-20,05168011CCCAACTTCATCAATATTT4-13-2CCCAacttcatcaatatTT11_1-23,96168011CCCAACTTCATCAATATTT2-15-2CCcaacttcatcaatatTT11_2-20,28168012ACCCAACTTCATCAATATT4-13-2ACCCaacttcatcaataTT12_1-23,64168112ACCCAACTTCATCAATATT2-15-2ACccaacttcatcaataTT12_2-19,18168113CCCAACTTCATCAATATT4-12-2CCCAacttcatcaataTT13_1-23,09168113CCCAACTTCATCAATATT2-14-2CCcaacttcatcaataTT13_2-19,41168114TACCCAACTTCATCAATAT2-15-2TAcccaacttcatcaatAT14_1-19,31168215TACCCAACTTCATCAATA2-14-2TAcccaacttcatcaaTA15_1-19,14168316TTACCCAACTTCATCAATA2-15-2TTacccaacttcatcaaTA16_1-19,74168317TTTACCCAACTTCATCAAT4-13-2TTTAcccaacttcatcaAT17_1-21,68168417TTTACCCAACTTCATCAAT2-15-2TTtacccaacttcatcaAT17_2-19,22168418ATACTTTACCCAACTTCAT3-13-3ATActttacccaacttCAT18_1-23,44168818ATACTTTACCCAACTTCAT2-15-2ATactttacccaacttcAT18_2-20,13168819TACTTTACCCAACTTCAT3-12-3TACtttacccaacttCAT19_1-22,78168819TACTTTACCCAACTTCAT2-14-2TActttacccaacttcAT19_2-19,30168820TTATACTTTACCCAACTTCA2-16-2TTatactttacccaacttCA20_1-21,40168921TCACTGTTCTGACTTT3-10-3TCActgttctgacTTT21_1-19,11171222TTCAATCTCTATCTCATCAT2-16-2TTcaatctctatctcatcAT22_1-19,42416923CTTCAATCTCTATCTCATCA4-14-2CTTCaatctctatctcatCA23_1-24,21417023CTTCAATCTCTATCTCATCA2-16-2CTtcaatctctatctcatCA23_2-22,04417024TTCAATCTCTATCTCATCA2-15-2TTcaatctctatctcatCA24_1-19,44417025CTTCAATCTCTATCTCATC2-15-2CTtcaatctctatctca TC25_1-19,87417126ACTTCAATCTCTATCTCAT3-13-3ACTtcaatctctatctCAT26_1-22,36417226ACTTCAATCTCTATCTCAT2-15-2ACttcaatctctatctcAT26_2-19,08417227CACTTCAATCTCTATCTCAT2-16-2CActtcaatctctatctcAT27_1-20,98417228ACTTCAATCTCTATCTCA2-12-4ACttcaatctctatCTCA28_1-21,96417328ACTTCAATCTCTATCTCA2-14-2ACttcaatctctatctCA28_2-19,10417329CACTTCAATCTCTATCTCA2-13-4CActtcaatctctatCTCA29_1-23,86417329CACTTCAATCTCTATCTCA2-15-2CActtcaatctctatctCA29_2-21,00417330ACACTTCAATCTCTATCTC2-15-2ACacttcaatctctatcTC30_1-19,38417431TACACTTCAATCTCTATCTC2-14-4TAcacttcaatctctaTCTC31_1-23,31417431TACACTTCAATCTCTATCTC2-16-2TAcacttcaatctctatcTC31_2-20,53417432TACACTTCAATCTCTATCT4-13-2TACActtcaatctctatCT32_1-22,34417533CTTTGTCTCTCTTTACT2-13-2CTttgtctctctttaCT33_1-19,36437434TATACCTTTCTTTAACCC3-12-3TATacctttctttaaCCC34_1-24,89811834TATACCTTTCTTTAACCC2-14-2TAtacctttctttaacCC34_2-20,83811834TATACCTTTCTTTAACCC1-3-1-7-1-1-1-1-2TataCctttcttTaAcCC34_3-21,63811634TATACCTTTCTTTAACCC1-4-1-6-1-3-2TatacCtttcttTaacCC34_4-21,31811634TATACCTTTCTTTAACCC1-2-1-1-1-7-2-1-2TatAcCtttctttAAcCC34_5-21,51811634TATACCTTTCTTTAACCC2-3-1-7-1-2-2TAtacCtttctttAacCC34_6-21,84811634TATACCTTTCTTTAACCC2-13-3TAtacctttctttaaCCC34_7-23,21811635TGTTTATACCCTTTCC2-12-2TGtttataccctttCC35_1-20,33921235TGTTTATACCCTTTCC4-10-2TGTTtataccctttCC35_2-22,69921236TCTCCTTTATGACTCC2-10-4TCtcctttatgaCTCC36_1-23,291083937CTTCTCCTTTATGACTC2-13-2CTtctcctttatgacTC37_1-19,261084038CCATTTATTTCCATTTATT4-13-2CCATttatttccatttaTT38_1-22,321556738CCATTTATTTCCATTTATT2-15-2CCatttatttccattta TT38_2-19,611556738CCATTTATTTCCATTTATT1-2-1-9-2-1-3CcaTttatttccaTTtATT38_3-20,021556738CCATTTATTTCCATTTATT1-1-1-1-1-8-1-1-1-1-2CcAtTtatttccaTtTaTT38_4-18,951556738CCATTTATTTCCATTTATT2-2-1-8-1-3-2CCatTtatttccaTttaTT38_5-20,351556738CCATTTATTTCCATTTATT1-2-3-6-1-3-3CcaTTTatttccAtttATT38_6-20,871556739CTTTCCATTTATTTCCATTT2-14-4CTttccatttatttccATTT39_1-23,141557039CTTTCCATTTATTTCCATTT1-13-1-1-1-1-2CtttccatttatttCcAtTT39_2-20,961557039CTTTCCATTTATTTCCATTT1-13-1-3-2CtttccatttatttCcatTT39_3-20,911557039CTTTCCATTTATTTCCATTT1-3-1-1-1-11-2CtttCcAtttatttccatTT39_4-20,961557039CTTTCCATTTATTTCCATTT1-1-1-3-1-9-1-1-2CtTtccAtttatttccAtTT39_5-20,541557040TCTTTCCATTTATTTCCATT2-14-4TCtttccatttatttcCATT40_1-24,621557140TCTTTCCATTTATTTCCATT2-13-1-1-3TCtttccatttatttCcATT40_2-23,391557140TCTTTCCATTTATTTCCATT2-13-1-2-2TCtttccatttatttCcaTT40_3-22,531557140TCTTTCCATTTATTTCCATT2-14-1-1-2TCtttccatttatttcCa TT40_4-22,341557140TCTTTCCATTTATTTCCATT2-3-1-11-3TCtttCcatttatttccATT40_5-23,391557140TCTTTCCATTTATTTCCATT2-4-1-10-3TCtttcCatttatttccATT40_6-23,201557140TCTTTCCATTTATTTCCATT2-3-1-12-2TCtttCcatttatttccaTT40_7-22,531557140TCTTTCCATTTATTTCCATT2-4-1-11-2TCtttcCatttatttcca TT40_8-22,341557141ATTACCCATCCGTTCT2-12-2ATtacccatccgttCT41_1-21,152196542GCATTAGGCACATTACAT3-12-3GCAttaggcacattaCAT42_1-23,962221143ATTATTATTTAACCTTCCTA2-16-2ATtattatttaaccttccTA43_1-19,283045144ACATTATTATTTAACCTTCC4-14-2ACA TtattatttaaccttCC44_1-22,843045344ACATTATTATTTAACCTTCC2-16-2ACattattatttaaccttCC44_2-20,133045345CATTATTATTTAACCTTCC4-13-2CATTattatttaaccttCC45_1-22,043045345CATTATTATTTAACCTTCC2-15-2CAttattatttaaccttCC45_2-19,553045346CCTCTGCTTATAACTTT2-13-2CCtctgcttataactTT46_1-19,153069947CTACTATACTTTCCTCT2-11-4CTactatactttcCTCT47_1-22,323071148GTTCTACTATACTTTCC4-11-2GTTCtactatactttCC48_1-21,693071448GTTCTACTATACTTTCC2-13-2GTtctactatactttCC48_2-19,213071448GTTCTACTATACTTTCC1-2-1-7-2-2-2GttCtactataCTttCC48_3-20,833071248GTTCTACTATACTTTCC2-9-1-3-2GTtctactataCtttCC48_4-20,203071248GTTCTACTATACTTTCC1-2-1-9-1-1-2GttCtactatactTtCC48_5-18,953071248GTTCTACTATACTTTCC2-1-1-10-3GTtCtactatacttTCC48_6-21,183071248GTTCTACTATACTTTCC1-3-1-10-2GttcTactatactttCC48_7-18,613071249CACCTGATAACAGACCCT3-12-3CACctgataacagacCCT49_1-26,383606850CACCTGATAACAGACC3-10-3CACctgataacagACC50_1-21,103607051CCCACCAAAGGATATATT3-12-3CCCaccaaaggatatATT51_1-23,473720852ACCAGCTACAGGAACCTC3-12-3ACCagctacaggaacCTC52_1-26,574613253CTATATCTCACTCCTATTT4-13-2CTATatctcactcctatTT53_1-23,074814353CTATATCTCACTCCTATTT2-13-4CTatatctcactcctATTT53_2-22,124814354CTATATCTCACTCCTATT2-14-2CTatatctcactcctaTT54_1-19,404814454CTATATCTCACTCCTATT2-12-4CTatatctcactccTATT54_2-22,284814454CTATATCTCACTCCTATT3-12-3CTAtatctcactcctATT54_3-21,444814455CTACTATATCTCACTCCTAT2-16-2CTactatatctcactcctAT55_1-22,004814555CTACTATATCTCACTCCTAT2-14-4CTactatatctcactcCTAT55_2-25,544814556TACTATATCTCACTCCTAT2-13-4TActatatctcactcCTAT56_1-23,294814557CTACTATATCTCACTCCTA2-15-2CTactatatctcactccTA57_1-21,914814658TACTATATCTCACTCCTA2-14-2TActatatctcactccTA58_1-19,664814658TACTATATCTCACTCCTA2-12-4TActatatctcactCCTA58_2-23,594814658TACTATATCTCACTCCTA3-12-3TACtatatctcactcCTA58_3-22,624814659CTACTATATCTCACTCCT2-14-2CTactatatctcactcCT59_1-21,254814759CTACTATATCTCACTCCT4-12-2CTACtatatctcactcCT59_2-23,874814760CTACTATATCTCACTCC2-13-2CTactatatctcactCC60_1-20,134814860CTACTATATCTCACTCC2-11-4CTactatatctcaCTCC60_2-23,004814860CTACTATATCTCACTCC3-11-3CTActatatctcacTCC60_3-22,564814861CCTACTATATCTCACTC2-11-4CCtactatatctcACTC61_1-21,934814962CTCCTACTATATCTCACTC4-13-2CTCCtactatatctcacTC62_1-25,694814963TCCTACTATATCTCACTC3-12-3TCCtactatatctcaCTC63_1-23,884814964CTCCTACTATATCTCACT4-12-2CTCCtactatatctcaCT64_1-24,874815064CTCCTACTATATCTCACT3-12-3CTCctactatatctcACT64_2-22,934815065TTTCCTCTCCTACTATATC2-15-2TTtcctctcctactata TC65_1-21,234815566ATCCATATCCTTTCCT3-10-3ATCcatatcctttCCT66_1-24,024816867CATCCATATCCTTTCCT4-11-2CATCcatatcctttcCT67_1-24,944816868ATCATCCATATCCTTTCC4-12-2ATCAtccatatcctttCC68_1-25,694816969CATCATCCATATCCTTTC4-12-2CATCatccatatccttTC69_1-23,324817069CATCATCCATATCCTTTC2-14-2CAtcatccatatccttTC69_2-20,724817069CATCATCCATATCCTTTC2-12-4CAtcatccatatccTTTC69_3-22,564817070TACATCATCCATATCCTTTC2-16-2TAcatcatccatatccttTC70_1-22,454817070TACATCATCCATATCCTTTC4-14-2TACAtcatccatatccttTC70_2-25,004817070TACATCATCCATATCCTTTC2-14-4TAcatcatccatatccTTTC70_3-24,294817071ACATCATCCATATCCTTT3-12-3ACAtcatccatatccTTT71_1-22,114817172CATCATCCATATCCTTT2-13-2CAtcatccatatcctTT72_1-19,044817172CATCATCCATATCCTTT4-11-2CATCatccatatcctTT72_2-21,644817173TACATCATCCATATCCTTT2-15-2TAcatcatccatatcctTT73_1-20,764817173TACATCATCCATATCCTTT2-13-4TAcatcatccatatcCTTT73_2-23,364817173TACATCATCCATATCCTTT3-13-3TACatcatccatatccTTT73_3-22,884817174ATACATCATCCATATCCTT2-15-2ATacatcatccatatccTT74_1-20,804817274ATACATCATCCATATCCTT4-13-2ATACatcatccatatccTT74_2-23,124817275TACATCATCCATATCCTT2-14-2TAcatcatccatatccTT75_1-19,974817275TACATCATCCATATCCTT4-12-2TACAtcatccatatccTT75_2-22,524817276TATACATCATCCATATCCTT2-16-2TAtacatcatccatatccTT76_1-21,364817277ATACATCATCCATATCCT3-12-3ATAcatcatccatatCCT77_1-24,154817377ATACATCATCCATATCCT2-14-2ATacatcatccatatcCT77_2-20,554817377ATACATCATCCATATCCT2-13-3ATacatcatccatatCCT77_3-22,924817378ATATACATCATCCATATCCT2-16-2ATatacatcatccatatcCT78_1-22,044817379TACATCATCCATATCCT2-11-4TAcatcatccataTCCT79_1-23,214817379TACATCATCCATATCCT2-13-2TAcatcatccatatcCT79_2-19,714817379TACATCATCCATATCCT4-11-2TACAtcatccatatcCT79_3-22,274817380TATACATCATCCATATCCT2-15-2TAtacatcatccatatcCT80_1-21,114817380TATACATCATCCATATCCT3-13-3TATacatcatccatatCCT80_2-25,154817380TATACATCATCCATATCCT4-13-2TATAcatcatccatatcCT80_3-24,014817381ATACATCATCCATATCC3-11-3AT Acatcatccata TCC81_1-21,794817482ATATACATCATCCATATCC4-13-2ATATacatcatccatatCC82_1-23,734817482ATATACATCATCCATATCC2-15-2ATatacatcatccatatCC82_2-20,934817483TATACATCATCCATATCC2-14-2TAtacatcatccatatCC83_1-20,004817483TATACATCATCCATATCC4-12-2TATAcatcatccatatCC83_2-22,904817484TATATACATCATCCATATCC2-16-2TAtatacatcatccatatCC84_1-21,494817484TATATACATCATCCATATCC4-14-2TATAtacatcatccatatCC84_2-24,294817485GCTTCATATTTCTCCA2-12-2GCttcatatttctcCA85_1-20,444934585GCTTCATATTTCTCCA2-11-3GCttcatatttctCCA85_2-22,814934586CATCTTGTTCTTTACCT2-13-2CAtcttgttctttacCT86_1-19,674958187TATATTCACCATTGCC2-10-4TAtattcaccatTGCC87_1-22,704972488CCTTATATTCACCATTG2-13-2CCttatattcaccatTG88_1-19,444972688CCTTATATTCACCATTG2-11-4CCttatattcaccATTG88_2-21,254972689CCTCCTTATATTCACC4-10-2CCTCcttatattcaCC89_1-24,644973090CCCTTCCTTTATTCAA3-10-3CCCttcctttattCAA90_1-23,865018991CCTTACTGTTAAATCCT2-13-2CCttactgttaaatcCT91_1-19,815047592CAGGCAGATAACCTCCAA3-12-3CAGgcagataacctcCAA92_1-25,315241993CAGCAGGCAGATAACCTC3-12-3CAGcaggcagataacCTC93_1-25,885242294CGAATCTTGACATACAGG3-12-3CGAatcttgacatacAGG94_1-21,475395595CTCATACTTGCTTTAAT4-11-2CTCAtacttgctttaAT95_1-19,106082195CTCATACTTGCTTTAAT2-13-2CTcatacttgctttaAT95_2-16,356082196ACATCTCATACTTGCTT2-11-4ACatctcatacttGCTT96_1-21,316082596ACATCTCATACTTGCTT2-13-2ACatctcatacttgcTT96_2-17,666082596ACATCTCATACTTGCTT2-12-3ACatctcatacttgCTT96_3-19,526082597ACATCTCATACTTGCT2-10-4ACatctcatactTGCT97_1-21,186082697ACATCTCATACTTGCT2-12-2ACatctcatacttgCT97_2-17,706082697ACATCTCATACTTGCT2-11-3ACatctcatacttGCT97_3-19,496082697ACATCTCATACTTGCT4-10-2ACATctcatacttgCT97_4-20,486082698TACATCTCATACTTGCT2-11-4TAcatctcatactTGCT98_1-22,336082698TACATCTCATACTTGCT2-13-2TAcatctcatacttgCT98_2-18,856082698TACATCTCATACTTGCT4-11-2TACAtctcatacttgCT98_3-21,406082699CCTACATCTCATACTTGC3-12-3CCTacatctcatactTGC99_1-26,296082799CCTACATCTCATACTTGC2-14-2CCtacatctcatacttGC99_2-22,986082799CCTACATCTCATACTTGC2-13-3CCtacatctcatactTGC99_3-24,676082799CCTACATCTCATACTTGC2-12-4CCtacatctcatacTTGC99_4-25,7060827100CTACATCTCATACTTGC3-11-3CTAcatctcatactTGC100_1-22,3360827100CTACATCTCATACTTGC2-13-2CTacatctcatacttGC100_2-19,4160827100CTACATCTCATACTTGC2-12-3CTacatctcatactTGC100_3-21,1060827101TACATCTCATACTTGC3-10-3TACatctcatactTGC101_1-19,9460827101TACATCTCATACTTGC2-12-2TAcatctcatacttGC101_2-17,1560827101TACATCTCATACTTGC2-11-3TAcatctcatactTGC101_3-18,8560827101TACATCTCATACTTGC4-10-2TACAtctcatacttGC101_4-19,7160827102CCTACATCTCATACTTG4-11-2CCTAcatctcatactTG102_1-22,5260828102CCTACATCTCATACTTG2-13-2CCtacatctcatactTG102_2-19,6760828102CCTACATCTCATACTTG3-12-2CCTacatctcatactTG102_3-21,2960828102CCTACATCTCATACTTG3-11-3CCTacatctcatacTTG102_4-22,3160828103ACCTACATCTCATACTT3-11-3ACCtacatctcataCTT103_1-21,9360829103ACCTACATCTCATACTT2-13-2ACctacatctcatacTT103_2-17,7660829103ACCTACATCTCATACTT2-11-4ACctacatctcatACTT103_3-20,0360829103ACCTACATCTCATACTT3-12-2ACCtacatctcatacTT103_4-20,2660829104CCTACATCTCATACTT3-10-3CCTacatctcataCTT104_1-21,5060829104CCTACATCTCATACTT2-12-2CCtacatctcatacTT104_2-18,2160829104CCTACATCTCATACTT2-10-4CCtacatctcatACTT104_3-20,4860829105TACCTACATCTCATACTT4-12-2TACCtacatctcatacTT105_1-22,4960829105TACCTACATCTCATACTT2-14-2TAcctacatctcatacTT105_2-18,8160829105TACCTACATCTCATACTT2-13-3TAcctacatctcataCTT105_3-20,4860829105TACCTACATCTCATACTT2-12-4TAcctacatctcatACTT105_4-21,0860829106TTACCTACATCTCATACTT3-13-3TTAcctacatctcataCTT106_1-22,3060829106TTACCTACATCTCATACTT2-15-2TTacctacatctcatacTT106_2-19,4060829106TTACCTACATCTCATACTT2-14-3TTacctacatctcataCTT106_3-21,0860829106TTACCTACATCTCATACTT2-13-4TTacctacatctcatACTT106_4-21,6760829107ACCTACATCTCATACT4-10-2ACCTacatctcataCT107_1-21,7260830107ACCTACATCTCATACT2-12-2ACctacatctcataCT107_2-17,6160830107ACCTACATCTCATACT3-11-2ACCtacatctcataCT107_3-20,1060830107ACCTACATCTCATACT2-10-4ACctacatctcaTACT107_4-20,1160830108TACCTACATCTCATACT4-11-2TACCtacatctcataCT108_1-22,3460830108TACCTACATCTCATACT2-13-2TAcctacatctcataCT108_2-18,6660830108TACCTACATCTCATACT3-12-2TACctacatctcataCT108_3-19,8560830108TACCTACATCTCATACT3-11-3TACctacatctcatACT108_4-20,4460830109TTACCTACATCTCATACT2-12-4TTacctacatctcaTACT109_1-21,7560830109TTACCTACATCTCATACT2-14-2TTacctacatctcataCT109_2-19,2560830109TTACCTACATCTCATACT3-13-2TTAcctacatctcataCT109_3-20,4860830109TTACCTACATCTCATACT3-12-3TTAcctacatctcatACT109_4-21,0860830110TTACCTACATCTCATAC3-11-3TTAcctacatctcaTAC110_1-19,5060831110TTACCTACATCTCATAC2-13-2TTacctacatctcatAC110_2-16,3760831111GTTACCTACATCTCATA2-11-4GTtacctacatctCATA111_1-21,6960832111GTTACCTACATCTCATA2-13-2GTtacctacatctcaTA111_2-18,7460832111GTTACCTACATCTCATA3-12-2GTTacctacatctcaTA111_3-19,9860832112GTTACCTACATCTCAT3-10-3GTTacctacatctCAT112_1-20,6960833112GTTACCTACATCTCAT2-12-2GTtacctacatctcAT112_2-17,3760833113ATATACCCAAAGGCACCT3-12-3ATAtacccaaaggcaCCT113_1-25,9962200114TCTACTCATCCTTTAACTCA2-14-4TCtactcatcctttaaCTCA114_1-25,6362251115CCTTAATCTGTATCACT2-13-2CCttaatctgtatcaCT115_1-19,5862286116CCATACACAGCACATA2-12-2CCatacacagcacaTA116_1-19,0462424117CTCCATACACAGCACAT2-13-2CTccatacacagcacAT117_1-20,0862425118CAGAATAATTCTCCTCC2-13-2CAgaataattctcctCC118_1-19,8662441119GTCCTACATATATACC4-10-2GTCCtacatatataCC119_1-22,0966380120TGCTTCCTTACTAACC4-10-2TGCTtccttactaaCC120_1-23,9366701120TGCTTCCTTACTAACC2-12-2TGcttccttactaaCC120_2-20,1066701121CCCTTTGTAATCATCT4-10-2CCCTttgtaatcatCT121_1-23,4466838122TCCCTTTGTAATCATCT2-13-2TCcctttgtaatcatCT122_1-19,9766838123CTGCCATCAATACCAT2-12-2CTgccatcaataccAT123_1-19,1468918124TCACTGCCATCAATACC2-13-2TCactgccatcaataCC124_1-21,3568920125ATTCTTACTTTATTCCTCA2-15-2ATtcttactttattcctCA125_1-20,1670033126TCACTTTCCAGATATCA4-11-2TCACtttccagatatCA126_1-21,6177567126TCACTTTCCAGATATCA2-13-2TCactttccagatatCA126_2-18,6577567127TCCTTCAAATTCCACATAC3-13-3TCCttcaaattccacaTAC127_1-24,0982053128ACATGTCCCTTTATATT4-11-2ACATgtccctttataTT128_1-20,8792323128ACATGTCCCTTTATATT2-13-2ACatgtccctttata TT128_2-17,6692323128ACATGTCCCTTTATATT3-12-2ACAtgtccctttataTT128_3-19,1392323128ACATGTCCCTTTATATT3-11-3ACAtgtccctttatATT128_4-20,0392323129ACATGTCCCTTTATAT3-10-3ACAtgtccctttaTAT129_1-20,1192324129ACATGTCCCTTTATAT2-12-2ACatgtccctttatAT129_2-16,7492324130CCAAGAAAGGAGCAAGCT3-12-3CCAagaaaggagcaaGCT130_1-25,2697146131TCCAAGAAAGGAGCAAGC3-12-3TCCaagaaaggagcaAGC131_1-24,1297147132CTCATCCCTCCAAGAAA4-11-2CTCAtccctccaagaAA132_1-22,5897156132CTCATCCCTCCAAGAAA2-13-2CTcatccctccaagaAA132_2-19,8397156132CTCATCCCTCCAAGAAA3-12-2CTCatccctccaagaAA132_3-21,1197156133TCATCCCTCCAAGAAA4-10-2TCATccctccaagaAA133_1-20,4197156133TCATCCCTCCAAGAAA2-12-2TCatccctccaagaAA133_2-17,6397156133TCATCCCTCCAAGAAA3-11-2TCAtccctccaagaAA133_3-19,0997156133TCATCCCTCCAAGAAA3-10-3TCAtccctccaagAAA133_4-19,8197156134CACCTCCCTATTACATAAA4-13-2CACCtccctattacataAA134_1-24,18100018134CACCTCCCTATTACATAAA2-15-2CAcctccctattacataAA134_2-20,51100018135CACCTCCCTATTACATAA4-12-2CACCtccctattacatAA135_1-23,75100019135CACCTCCCTATTACATAA2-14-2CAcctccctattacatAA135_2-20,07100019136CCTCCCTATTACATAA2-12-2CCtccctattacatAA136_1-18,40100019137CTAAATCTTCCAATTCATA2-15-2CTaaatcttccaattcaTA137_1-18,12106139138TATCCCTTGATTATCCT2-13-2TAtcccttgattatcCT138_1-20,68109406139CCTCTTTGTCAAATACT2-13-2CCtctttgtcaaataCT139_1-19,30110768140CAGCTTATTTACCTCTT2-13-2CAgcttatttacctcTT140_1-19,30114828141ACTCTTTACCTCTAACACT4-13-2ACTCtttacctctaacaCT141_1-24,26117468142TTACTCTTTACCTCTAACAC3-14-3TTActctttacctctaaCAC142_1-23,23117469143CCAACCTAATACCTTAATA2-15-2CCaacctaataccttaaTA143_1-20,27118639144TACCAACCTAATACCTTAA2-15-2TAccaacctaataccttAA144_1-18,32118641145CCAATACCCACAAACC3-10-3CCAatacccacaaACC145_1-23,17124162145CCAATACCCACAAACC2-12-2CCaatacccacaaaCC145_2-20,85124162146CCATTATTCTACTTTGT3-11-3CCAttattctacttTGT146_1-21,79125501146CCATTATTCTACTTTGT2-13-2CCattattctactttGT146_2-18,63125501147CATTTCCTTATCTTCACA2-14-2CAtttccttatcttcaCA147_1-20,39125529148TCATTTCCTTATCTTCACA4-13-2TCATttccttatcttcaCA148_1-24,13125529149AATAATTCCTCATTTCCT2-14-2AAtaattcctcatttcCT149_1-18,01125539150ACAATAATTCCTCATTTCC3-13-3ACAataattcctcattTCC150_1-22,71125540150ACAATAATTCCTCATTTCC2-15-2ACaataattcctcatttCC150_2-20,23125540151TATTGAACCAATTCTA3-10-3TATtgaaccaattCTA151_1-16,934806152CATATTGAACCAATTC4-10-2CATAttgaaccaatTC152_1-16,324808153TCATATTGAACCAATT4-10-2TCATattgaaccaaTT153_1-16,144809154CATCATATTGAACCAA2-10-4CAtcatattgaaCCAA154_1-17,654811155TCATCATATTGAACCA3-10-3TCAtcatattgaaCCA155_1-19,404812156CACAATCAACAACAAATA4-12-2CACAatcaacaacaaaTA156_1-16,164972157TACACAATCAACAACAAAT4-13-2TACAcaatcaacaacaaAT157_1-16,764973158CTGTACACAATCAACA4-10-2CTGTacacaatcaaCA158_1-19,054979159CACTAATAATTCACTTT4-11-2CACTaataattcactTT159_1-16,395058160CAACATTATTGACACT2-10-4CAacattattgaCACT160_1-17,175071161AAACTTTCCCAACATTAT2-12-4AAactttcccaacaTTAT161_1-18,695078162TCCTATATTCTCTTAAA4-11-2TCCTatattctcttaAA162_1-18,585094163TTTCCTATATTCTCTTA4-11-2TTTCctatattctctTA163_1-18,695096164CAAGTTTCCTATATTCT4-11-2CAAGtttcctatattCT164_1-19,975100165CAAGTTTCCTATATTC4-10-2CAAGtttcctatatTC165_1-17,475101166CATTCTATCTGCCAAA2-10-4CAttctatctgcCAAA166_1-18,365218167CCATTCTATCTGCCAAA2-11-4CCattctatctgcCAAA167_1-22,085218168TATAGCCATTCTATCT4-10-2TATAgccattctatCT168_1-20,635224169TTATAGCCATTCTATCT4-11-2TTATagccattctatCT169_1-20,825224169TTATAGCCATTCTATCT1-10-3-1-2TtatagccattCTAtCT169_2-20,515224169TTATAGCCATTCTATCT2-9-1-2-3TTatagccattCtaTCT169_3-20,125224169TTATAGCCATTCTATCT1-1-1-8-2-1-3TtAtagccattCT a TCT169_4-20,595224169TTATAGCCATTCTATCT1-3-1-6-2-2-2TtatAgccattCTatCT169_5-19,975224169TTATAGCCATTCTATCT3-8-1-3-2TTAtagccattCtatCT169_6-20,135224169TTATAGCCATTCTATCT1-10-2-2-2TtatagccattCTatCT169_7-19,375224169TTATAGCCATTCTATCT2-9-1-1-4TTatagccattCtATCT169_8-21,025224169TTATAGCCATTCTATCT1-1-1-8-1-1-4TtAtagccattCtATCT169_9-19,885224169TTATAGCCATTCTATCT1-2-1-7-1-1-4TtaTagccattCtATCT169_10-20,655224169TTATAGCCATTCTATCT1-3-1-6-1-1-4TtatAgccattCtATCT169_11-20,385224169TTATAGCCATTCTATCT1-10-1-1-4TtatagccattCtATCT169_12-19,785224169TTATAGCCATTCTATCT3-8-1-1-1-1-2TTAtagccattCtAtCT169_13-20,225224169TTATAGCCATTCTATCT2-1-1-7-1-1-1-1-2TTaTagccattCtAtCT169_14-19,965224169TTATAGCCATTCTATCT2-2-1-6-1-1-1-1-2TTatAgccattCtAtCT169 15-19,695224169TTATAGCCATTCTATCT2-9-1-1-1-1-2TTatagccattCtAtCT169_16-19,095224169TTATAGCCATTCTATCT1-2-2-6-1-1-1-1-2TtaTAgccattCtAtCT169 17-20,355224169TTATAGCCATTCTATCT1-2-1-7-1-1-1-1-2TtaTagccattCtAtCT169_18-18,725224169TTATAGCCATTCTATCT1-3-1-6-1-1-1-1-2TtatAgccattCtAtCT169 19-18,455224169TTATAGCCATTCTATCT2-2-1-6-1-2-3TTatAgccattCtaTCT169_20-20,715224169TTATAGCCATTCTATCT1-1-2-7-1-2-3TtATagccattCtaTCT169 21-20,655224169TTATAGCCATTCTATCT1-1-1-1-1-6-1-2-3TtAtAgccattCtaTCT169_22-19,575224169TTATAGCCATTCTATCT1-1-1-8-1-2-3TtAtagccattCtaTCT169_23-18,985224169TTATAGCCATTCTATCT4-7-1-3-2TTATagccattCtatCT169_24-21,805224169TTATAGCCATTCTATCT3-1-1-6-1-3-2TTAtAgccattCtatCT169_25-20,725224169TTATAGCCATTCTATCT2-1-1-7-1-3-2TTaTagccattCtatCT169 26-19,865224169TTATAGCCATTCTATCT2-2-1-6-1-3-2TTatAgccattCtatCT169_27-19,595224169TTATAGCCATTCTATCT2-9-1-3-2TTatagccattCtatCT169_28-18,995224169TTATAGCCATTCTATCT1-1-3-6-1-3-2TtATAgccattCtatCT169_29-21,165224169TTATAGCCATTCTATCT1-1-2-7-1-3-2TtATagccattCtatCT169 30-19,535224169TTATAGCCATTCTATCT1-1-1-1-1-6-1-3-2TtAtAgccattCtatCT169_31-18,455224169TTATAGCCATTCTATCT1-2-2-6-1-3-2TtaTAgccattCtatCT169_32-20,255224169TTATAGCCATTCTATCT1-2-1-7-1-3-2TtaTagccattCtatCT169_33-18,625224169TTATAGCCATTCTATCT1-3-1-6-1-3-2TtatAgccattCtatCT169_34-18,355224169TTATAGCCATTCTATCT1-1-1-9-5TtAtagccattcTATCT169_35-20,885224169TTATAGCCATTCTATCT2-10-2-1-2TTatagccattcTAtCT169_36-20,095224169TTATAGCCATTCTATCT1-1-1-9-2-1-2TtAtagccattcTAtCT169_37-18,955224169TTATAGCCATTCTATCT1-2-1-8-2-1-2TtaTagccattcTAtCT169_38-19,725224169TTATAGCCATTCTATCT1-3-1-7-2-1-2TtatAgccattcTAtCT169_39-19,445224169TTATAGCCATTCTATCT1-11-2-1-2TtatagccattcTAtCT169 40-18,855224169TTATAGCCATTCTATCT3-9-1-1-3TTAtagccattcTaTCT169 41-21,215224169TTATAGCCATTCTATCT1-1-1-9-1-1-3TtAtagccattcTaTCT169 42-18,945224169TTATAGCCATTCTATCT3-9-1-2-2TTAtagccattcTatCT169 43-20,095224169TTATAGCCATTCTATCT1-2-1-8-1-2-2TtaTagccattcTatCT169 44-18,585224169TTATAGCCATTCTATCT1-3-1-7-1-2-2TtatAgccattcTatCT169 45-18,315224169TTATAGCCATTCTATCT1-1-1-10-4TtAtagccattctATCT169_46-18,905224169TTATAGCCATTCTATCT3-10-1-1-2TTAtagccattctAtCT169 47-19,245224169TTATAGCCATTCTATCT2-11-1-1-2TTatagccattctAtCT169_48-18,115224169TTATAGCCATTCTATCT1-2-2-8-1-1-2TtaTAgccattctAtCT169_49-19,375224169TTATAGCCATTCTATCT3-1-1-10-2TTAtAgccattctatCT169_50-19,745224169TTATAGCCATTCTATCT3-12-2TTAtagccattctatCT169_51-19,155224169TTATAGCCATTCTATCT2-1-2-10-2TTaTAgccattctatCT169 52-20,515224169TTATAGCCATTCTATCT2-1-1-11-2TTaTagccattctatCT169_53-18,885224169TTATAGCCATTCTATCT2-2-1-10-2TTatAgccattctatCT169_54-18,615224169TTATAGCCATTCTATCT2-13-2TTatagccattctatCT169_55-18,025224169TTATAGCCATTCTATCT1-1-3-10-2TtATAgccattctatCT169_56-20,185224169TTATAGCCATTCTATCT1-1-2-11-2TtATagccattctatCT169_57-18,555224169TTATAGCCATTCTATCT2-9-3-1-2TTatagccattCTAtCT169_58-21,755224169TTATAGCCATTCTATCT1-1-1-8-2-2-2TtAtagccattCTatCT169_59-19,475224169TTATAGCCATTCTATCT1-2-2-6-2-2-2TtaTAgccattCTatCT169_60-21,875224169TTATAGCCATTCTATCT1-1-3-6-1-1-1-1-2TtATAgccattCtAtCT169_61-21,255224169TTATAGCCATTCTATCT3-8-1-2-3TTAtagccattCtaTCT169_62-21,255224170ATTTAAATTTCCAAACATT2-13-4ATttaaatttccaaaCATT170_1-16,825427171GCTAATTTAAATTTCC4-10-2GCTAatttaaatttCC171_1-18,505434172ATCAATATCTTCTCAC3-10-3ATCaatatcttctCAC172_1-17,105785173TATCAATATCTTCTCA2-10-4TAtcaatatcttCTCA173_1-17,555786174CTACAAATTCAATTTACT2-12-4CTacaaattcaattTACT174_1-17,386341175TCTTACTCTGACTTTCCA2-14-2TCttactctgactttcCA175_1-21,476694176TCTTACTCTGACTTTCC2-12-3TCttactctgacttTCC176_1-21,536695177AAATTTCCAAACCTTTC2-11-4AAatttccaaaccTTTC177_1-16,306958178CTTCTTGTTTATCCCAA2-11-4CTtcttgtttatcCCAA178_1-22,777159179TTCTTGTTTATCCCAA2-10-4TTcttgtttatcCCAA179_1-20,177159180ATGCTTCTAACTAACA4-10-2ATGCttctaactaaCA180_1-19,217720181CTTTAATGCTTCTAACT4-11-2CTTTaatgcttctaaCT181_1-18,497724182CCTTTAATGCTTCTAAC2-11-4CCtttaatgcttcTAAC182_1-20,067725183CTTTAATGCTTCTAAC2-10-4CTttaatgcttcTAAC183_1-16,077725184TTCCTTTAATGCTTCTA4-11-2TTCCtttaatgcttcTA184_1-21,597727185TATACCTTTCTTTAACCCT2-15-2TAtacctttctttaaccCT185_1-22,038117186ATACCTTTCTTTAACCC4-11-2AT ACctttctttaacCC186_1-22,688118187TTATACCTTTCTTTAACC4-12-2TTATacctttctttaaCC187_1-21,528119188TTTATACCTTTCTTTAAC2-12-4TTtatacctttcttTAAC188_1-17,018120189TCAAGAATTCTCTCCTT2-11-4TCaagaattctctCCTT189_1-21,298571190TTCAAGAATTCTCTCC2-10-4TTcaagaattctCTCC190_1-19,388573191CTTCAAGAATTCTCTC2-10-4CTtcaagaattcTCTC191_1-18,008574192TCTTCAAGAATTCTCT2-10-4TCttcaagaattCTCT192_1-18,468575193ATCTTCAAGAATTCTC3-10-3ATCttcaagaattCTC193_1-17,048576194TTTCTTACTATCTTCA4-10-2TTTCttactatcttCA194_1-17,478585195CCTTTAGCATTTCTATT2-11-4CCtttagcatttcTATT195_1-21,728819196TCCTTTAGCATTTCTAT3-11-3TCCtttagcatttcTAT196_1-22,398820197GTTCTCTTTATTTCTTCT2-12-4GTtctctttatttcTTCT197_1-21,768887198TTTACTGTCAACTCCT2-10-4TTtactgtcaacTCCT198_1-20,839150199TTTCCAATGAATCTAT2-10-4TTtccaatgaatCTAT199 1-16,619201200CCTTTCCAATGAATCTA2-11-4CCtttccaatgaaTCTA200_1-22,349202201CTTTCCAATGAATCTA2-10-4CTttccaatgaaTCTA201_1-18,349202202CCTTTCCAATGAATCT3-10-3CCTttccaatgaaTCT202_1-21,309203203TTATACCCTTTCCAAT2-10-4TTataccctttcCAAT203_1-19,619209204GTTTATACCCTTTCCAA3-11-3GTTtataccctttcCAA204_1-21,889210205TTTATACCCTTTCCAA2-10-4TTtataccctttCCAA205_1-20,509210206GTTTATACCCTTTCCA2-11-3GTttataccctttCCA206_1-22,699211207TGTTTATACCCTTTCCA3-12-2TGTttataccctttcCA207_1-22,809211208ACTGTTTATACCCTTTCC2-14-2ACtgtttataccctttCC208_1-22,969212208ACTGTTTATACCCTTTCC1-11-1-3-2ActgtttataccCtttCC208_2-22,459212208ACTGTTTATACCCTTTCC1-2-1-10-1-1-2ActGtttataccctTtCC208_3-22,179212208ACTGTTTATACCCTTTCC1-2-1-1-1-10-2ActGtTtataccctttCC208_4-22,179212208ACTGTTTATACCCTTTCC1-2-1-12-2ActGtttataccctttCC208_5-21,879212208ACTGTTTATACCCTTTCC1-3-1-11-2Actg TttataccctttCC208_6-22,229212208ACTGTTTATACCCTTTCC1-15-2ActgtttataccctttCC208_7-21,569212209ACTGTTTATACCCTTTC4-11-2ACTGtttatacccttTC209_1-21,659213209ACTGTTTATACCCTTTC1-11-1-2-2ActgtttataccCttTC209_2-18,259213209ACTGTTTATACCCTTTC1-1-1-8-1-1-1-1-2AcTgtttatacCcTtTC209_3-19,569213209ACTGTTTATACCCTTTC1-2-1-9-4ActGtttatacccTTTC209_4-19,519213209ACTGTTTATACCCTTTC1-3-1-6-1-2-3Actg TttatacCctTTC209_5-19,519213209ACTGTTTATACCCTTTC2-9-1-3-2ACtgtttatacCcttTC209_6-19,439213209ACTGTTTATACCCTTTC1-2-1-7-1-3-2ActGtttatacCcttTC209_7-18,359213209ACTGTTTATACCCTTTC1-3-1-8-1-1-2ActgTttatacccTtTC209_8-18,539213209ACTGTTTATACCCTTTC1-11-1-1-3ActgtttataccCtTTC209_9-19,069213209ACTGTTTATACCCTTTC2-10-1-2-2ACtgtttataccCttTC209_10-19,649213210AACTGTTTATACCCTTT4-11-2AACTgtttataccctTT210_1-19,519214211TATGACTCCAATAATC3-10-3TATgactccaataATC211_1-16,5710832212CTCCTTTATGACTCCAA4-11-2CTCCtttatgactccAA212_1-22,7410837213CTCCTTTATGACTCCA3-11-2CTCctttatgactcCA213_1-21,5010838214CCATTATTTCTTAAATA4-11-2CCATtatttcttaaaTA214_1-17,5610877215ATTTCATATTACTAACTA2-12-4ATttcatattactaACTA215_1-16,6411434216CATTTCATATTACTAACT3-12-3CATttcatattactaACT216_1-17,7011435217TCATTTCATATTACTAAC4-12-2TCATttcatattactaAC217_1-16,7211436218ATCATTTCATATTACTA3-11-3ATCatttcatattaCTA218_1-17,2311438219TTATCATTTCATATTACT4-12-2TTATcatttcatattaCT219_1-17,7711439220TGTACTTTCCTTTACCA2-13-2TGtactttcctttacCA220_1-20,3711464221TATACACCATCATTATA4-11-2TATAcaccatcattaTA221_1-18,4811507222TTATACACCATCATTAT3-11-3TTAtacaccatcatTAT222_1-17,8311508223TATTTATACACCATCAT3-11-3TATttatacaccatCAT223_1-18,5411511224TTATTTATACACCATC2-10-4TTatttatacacCATC224_1-16,6011513225AATTATTTATACACCAT2-11-4AAttatttatacaCCAT225_1-16,8211514226CATGACACTTACATAA3-10-3CATgacacttacaTAA226_1-16,2611736227AGTTCACTACTATTAC3-10-3AGTtcactactatTAC227_1-17,5512361228ATAAGCTTACCTCATA2-10-4ATaagcttacctCATA228_1-19,3212794229TATAAGCTTACCTCAT3-10-3TATaagcttacctCAT229_1-19,3212795230ATATAAGCTTACCTCA4-10-2ATATaagcttacctCA230_1-19,3212796231CTTCCCTTTGATAACAT3-11-3CTTccctttgataaCAT231_1-21,1912894232TTCCCTTTGATAACAT4-10-2TTCCctttgataacAT232_1-19,2712894233CCTTCCCTTTGATAACA2-12-3CCttccctttgataACA233_1-23,0612895234CTTCCCTTTGATAACA4-10-2CTTCcctttgataaCA234_1-20,5112895235CCTTCCCTTTGATAAC3-11-2CCTtccctttgataAC235_1-20,9612896236TTGATTCAATTCCCTTA2-11-4TTgattcaattccCTTA236_1-20,4813223236TTGATTCAATTCCCTTA2-9-1-1-1-1-2TTgattcaattCcCtTA236_2-19,5413223236TTGATTCAATTCCCTTA2-10-1-1-3TTgattcaattcCcTTA236_3-19,5913223236TTGATTCAATTCCCTTA2-1-1-8-1-2-2TTgAttcaattcCctTA236_4-19,0613223236TTGATTCAATTCCCTTA2-2-1-7-1-2-2TTgaTtcaattcCctTA236_5-19,0013223236TTGATTCAATTCCCTTA2-9-1-3-2TTgattcaattCcctTA236_6-18,6513223236TTGATTCAATTCCCTTA1-2-2-6-2-2-2TtgATtcaattCCctTA236_7-21,3713223236TTGATTCAATTCCCTTA2-1-1-7-1-1-1-1-2TTgAttcaattCcCtTA236_8-20,0413223236TTGATTCAATTCCCTTA1-1-2-7-1-1-1-1-2TtGAttcaattCcCtTA236_9-20,1013223236TTGATTCAATTCCCTTA1-2-1-9-4TtgAttcaattccCTTA236_10-19,6713223236TTGATTCAATTCCCTTA1-3-1-6-1-1-1-1-2TtgaTtcaattCcCtTA236 11-18,6713223236TTGATTCAATTCCCTTA2-10-1-2-2TTgattcaattcCctTA236_12-18,5613223236TTGATTCAATTCCCTTA1-2-2-7-2-1-2TtgATtcaattcCCtTA236_13-21,4913223236TTGATTCAATTCCCTTA1-1-2-8-1-2-2TtGAttcaattcCctTA236_14-19,1313223236TTGATTCAATTCCCTTA2-11-1-1-2TTgattcaattccCtTA236_15-18,7713223236TTGATTCAATTCCCTTA1-1-1-1-1-8-1-1-2TtGaTtcaattccCtTA236_16-18,0713223236TTGATTCAATTCCCTTA1-1-2-7-2-2-2TtGAttcaattCCctTA236_17-21,5013223236TTGATTCAATTCCCTTA1-2-1-7-1-1-4TtgAttcaattCcCTTA236_18-20,4413223236TTGATTCAATTCCCTTA3-8-1-1-1-1-2TTGattcaattCcCtTA236_19-20,6013223236TTGATTCAATTCCCTTA2-2-1-6-1-3-2TTgaTtcaattCcctTA236_20-19,0913223236TTGATTCAATTCCCTTA2-2-1-7-2-1-2TTgaTtcaattcCCtTA236 21-21,4913223237ATTGATTCAATTCCCTT2-11-4ATtgattcaattcCCTT237_1-21,2813224237ATTGATTCAATTCCCTT3-8-3-1-2ATTgattcaatTCCcTT237_2-22,7813224237ATTGATTCAATTCCCTT1-1-1-8-3-1-2AtTgattcaatTCCcTT237_3-21,0213224237ATTGATTCAATTCCCTT1-2-1-8-2-1-2AttGattcaattCCcTT237_4-19,4013224237ATTGATTCAATTCCCTT1-3-1-7-2-1-2AttgAttcaattCCcTT237_5-19,7413224237ATTGATTCAATTCCCTT1-2-1-7-2-1-3AttGattcaatTCcCTT237_6-19,6713224237ATTGATTCAATTCCCTT2-2-1-7-1-1-3ATtgAttcaattCcCTT237_7-20,2713224237ATTGATTCAATTCCCTT1-1-1-9-1-1-3AtTgattcaattCcCTT237_8-19,3213224237ATTGATTCAATTCCCTT1-3-1-7-1-1-3AttgAttcaattCcCTT237_9-19,0213224237ATTGATTCAATTCCCTT1-1-1-1-1-7-2-1-2AtTgAttcaattCCcTT237_10-20,5313224237ATTGATTCAATTCCCTT1-2-2-7-2-1-2AttGAttcaattCCcTT237_11-21,1113224237ATTGATTCAATTCCCTT1-2-1-8-1-1-3AttGattcaattCcCTT237_12-18,6813224237ATTGATTCAATTCCCTT1-1-2-8-1-2-2AtTGattcaattCccTT237_13-18,8113224237ATTGATTCAATTCCCTT3-10-1-1-2ATTgattcaattcCcTT237_14-19,4213224237ATTGATTCAATTCCCTT1-1-2-9-4AtTGattcaattcCCTT237_15-21,8913224237ATTGATTCAATTCCCTT2-2-1-8-1-1-2ATtgAttcaattcCcTT237_16-18,6113224237ATTGATTCAATTCCCTT1-2-2-6-3-1-2AttGAttcaatTCCcTT237_17-22,0913224237ATTGATTCAATTCCCTT1-1-1-8-2-1-3AtTgattcaatTCcCTT237_18-20,3013224237ATTGATTCAATTCCCTT1-1-1-9-2-1-2AtTgattcaattCCcTT237_19-20,0313224237ATTGATTCAATTCCCTT1-1-1-1-1-7-1-1-3AtTgAttcaattCcCTT237_20-19,8213224237ATTGATTCAATTCCCTT3-1-1-8-1-1-2ATTgAttcaattcCcTT237_21-19,9213224238TTGATTCAATTCCCTT2-10-4TTgattcaattcCCTT238_1-20,5213224239TATTGATTCAATTCCCT2-11-4TAttgattcaattCCCT239_1-22,8213225239TATTGATTCAATTCCCT3-9-2-1-2TATtgattcaatTCcCT239_2-21,1713225239TATTGATTCAATTCCCT2-9-1-1-1-1-2TAttgattcaaTtCcCT239_3-19,3713225239TATTGATTCAATTCCCT1-1-2-7-3-1-2TaTTgattcaaTTCcCT239_4-21,4913225239TATTGATTCAATTCCCT1-3-1-6-3-1-2TattGattcaaTTCcCT239_5-19,9013225239TATTGATTCAATTCCCT2-9-1-2-3TAttgattcaaTtcCCT239_6-20,8913225239TATTGATTCAATTCCCT1-10-1-2-3TattgattcaaTtcCCT239_7-19,7613225239TATTGATTCAATTCCCT1-1-1-1-1-8-1-1-2TaTtGattcaattCcCT239_8-18,4113225239TATTGATTCAATTCCCT1-2-2-8-1-1-2TatTGattcaattCcCT239_9-19,6613225239TATTGATTCAATTCCCT1-2-1-9-1-1-2TatTgattcaattCcCT239_10-18,6013225239TATTGATTCAATTCCCT2-2-1-10-2TAttGattcaattccCT239_11-18,3313225239TATTGATTCAATTCCCT1-12-4TattgattcaattCCCT239_12-21,6913225239TATTGATTCAATTCCCT2-1-1-9-1-1-2TAtTgattcaattCcCT239_13-19,7313225239TATTGATTCAATTCCCT2-12-3TAttgattcaattcCCT239_14-20,4513225239TATTGATTCAATTCCCT1-2-1-10-3TatTgattcaattcCCT239_15-20,1113225239TATTGATTCAATTCCCT1-1-3-10-2TaTTGattcaattccCT239_16-19,8413225239TATTGATTCAATTCCCT1-1-1-1-1-6-3-1-2TaTtGattcaaTTCcCT239_17-20,3413225239TATTGATTCAATTCCCT2-2-1-6-1-1-1-1-2TAttGattcaaTtCcCT239_18-19,5413225239TATTGATTCAATTCCCT2-1-1-8-2-1-2TAtTgattcaatTCcCT239_19-20,7213225239TATTGATTCAATTCCCT1-1-2-9-1-1-2TaTTgattcaattCcCT239_20-19,5513225239TATTGATTCAATTCCCT2-1-1-10-3TAtTgattcaattcCCT239_21-21,2413225240TATTGATTCAATTCCC3-10-3TATtgattcaattCCC240_1-20,5813226241GCACATTCTTTCTATAC3-11-3GCAcattctttctaTAC241_1-21,1715115241GCACATTCTTTCTATAC1-1-3-6-2-2-2GcACAttctttCTatAC241_2-20,6815115241GCACATTCTTTCTATAC1-1-1-1-1-6-1-2-3GcAcAttctttCtaTAC241_3-18,4615115241GCACATTCTTTCTATAC1-1-2-7-1-2-3GcACattctttCtaTAC241_4-19,4915115241GCACATTCTTTCTATAC2-9-1-3-2GCacattctttCtatAC241_5-18,6815115241GCACATTCTTTCTATAC1-1-3-8-4GcACAttctttctAT AC241_6-20,8915115241GCACATTCTTTCTATAC2-2-1-9-3GCacAttctttctaTAC241_7-19,6615115241GCACATTCTTTCTATAC2-1-1-11-2GCaCattctttctatAC241 8-18,3915115241GCACATTCTTTCTATAC1-1-3-9-3GcACAttctttctaTAC241_9-19,9815115241GCACATTCTTTCTATAC3-12-2GCAcattctttctatAC241_10-19,2715115241GCACATTCTTTCTATAC1-1-1-1-1-6-1-1-4GcAcAttctttCtATAC241_11-19,3615115241GCACATTCTTTCTATAC3-8-1-1-1-1-2GCAcattctttCtAtAC241_12-20,3415115241GCACATTCTTTCTATAC2-1-1-7-1-2-3GCaCattctttCtaTAC241_13-21,2715115241GCACATTCTTTCTATAC1-2-2-8-4GcaCAttctttctATAC241_14-20,3315115241GCACATTCTTTCTATAC1-1-3-10-2GcACAttctttctatAC241_15-18,0815115242GAATTTCAACTACTAT2-10-4GAatttcaactaCTAT242_1-16,1315258243CCATTTATTTCCATTTAT3-12-3CCAtttatttccattTAT243 1-21,9215568244TTTCCATTTATTTCCATTT4-13-2TTTCcatttatttccatTT244_1-20,9315570244TTTCCATTTATTTCCATTT1-4-1-7-1-1-4TttccAtttatttCcATTT244_2-20,4815570244TTTCCATTTATTTCCATTT2-1-1-10-2-1-2TTtCcatttatttcCAtTT244_3-21,4715570244TTTCCATTTATTTCCATTT1-2-1-1-1-7-1-3-2TttCcAtttatttCcatTT244_4-19,4315570244TTTCCATTTATTTCCATTT2-2-2-11-2TTtcCAtttatttccatTT244_5-20,7015570245CTTTCCATTTATTTCCAT3-12-3CTTtccatttatttcCAT245_1-22,3115572246TCTTTCCATTTATTTCCA4-12-2TCTTtccatttatttcCA246_1-22,7415573247ATCTTTCCATTTATTTCC3-12-3A TCtttccatttattTCC247_1-22,8515574248TTCCATGCAAACTTTA4-10-2TTCCatgcaaacttTA248_1-19,0115722249CAGTTTAAATTCACAC3-10-3CAGtttaaattcaCAC249_1-16,6816597250CTATTCCAGTTTAAAT4-10-2CTATtccagtttaaAT250_1-16,8616603251TGCAAATACCTCTTCA4-10-2TGCAaatacctcttCA251_1-21,4916730252CTAAATAGATTCCACT2-10-4CTaaatagattcCACT252_1-17,9516849253TATTGATATTTACTCT2-10-4TAttgatatttaCTCT253_1-16,3217089254CCTTAGTATTACAATT4-10-2CCTTagtattacaaTT254_1-17,4317401255CTATTCAATAAACTAAACA4-13-2CTATtcaataaactaaaCA255_1-16,4524290256CAGCTATTCAATAAAC4-10-2CAGCtattcaataaAC256_1-16,9424296257TATAGACCCAAACTAT3-10-3TATagacccaaacTAT257_1-18,1524811258TAATCCCATACATCTAT2-11-4TAatcccatacatCTAT258_1-20,4525032259ATAATCCCATACATCTA3-11-3ATAatcccatacatCTA259_1-20,4525033260ATCTCAACTACCATTT4-10-2ATCTcaactaccatTT260_1-18,1425250261AATCTCAACTACCATT4-10-2AATCtcaactaccaTT261_1-16,7625251262ACAACTTCTATCATAC3-10-3ACAacttctatcaTAC262_1-16,3325718263GAACAACTTCTATCAT2-10-4GAacaacttctaTCAT263_1-16,9425720264TGAACAACTTCTATCA3-10-3TGAacaacttcta TCA264_1-17,3625721265TACACAAATACTTAAATCA4-13-2TACAcaaatacttaaatCA265_1-16,9326331266TTAAGCTTTCACCTAT2-10-4TTaagctttcacCTAT266_1-19,3627165267AAACTCTTGCATCTACT2-13-2AAactcttgcatctaCT267_1-16,6527248268AAATTTCTCAACCTAAATTT2-14-4AAatttctcaacctaaATTT268_1-16,7829330269CCAACATAGATCCTCT2-10-4CCaacatagatcCTCT269_1-22,4929635270TCCAACATAGATCCTCT2-11-4TCcaacatagatcCTCT270_1-22,8129635271CTCCAACATAGATCCTC3-11-3CTCcaacatagatcCTC271_1-22,8129636272TCCAACATAGATCCTC2-10-4TCcaacatagatCCTC272_1-21,6929636273CTCCAACATAGATCCT3-10-3CTCcaacatagatCCT273_1-22,6829637274TCTCCAACATAGATCCT4-11-2TCTCcaacatagatcCT274_1-22,8129637275ATTCTCAATTGCACTT4-10-2ATTCtcaattgcacTT275_1-17,9029661276TATTCTCAATTGCACTT4-11-2TATTctcaattgcacTT276_1-18,5429661277TCACCTAATAGCACCA2-10-4TCacctaatagcACCA277_1-21,9929684278TTCACCTAATAGCACCA2-11-4TTcacctaatagcACCA278_1-22,5329684279CATTATTATTTAACCTT2-11-4CAttattatttaaCCTT279_1-17,8330455280ACATTATTATTTAACCT3-11-3ACAttattatttaaCCT280_1-18,0530456281TACATTATTATTTAACC4-11-2TACAttattatttaaCC281_1-16,8030457282CATTTACATTATTATTTAAC2-14-4CAtttacattattattTAAC282_1-16,4430458283CTCATTTACATTATTATT4-12-2CTCAtttacattattaTT283_1-17,3330462284TATCTCATTTACATTATT4-12-2TATCtcatttacattaTT284_1-17,6230465285ATCATTCTCAACAATTA4-11-2ATCAttctcaacaatTA285_1-17,0430601285ATCATTCTCAACAATTA4-7-6ATCAttctcaaCAATTA285_2-21,4830601285ATCATTCTCAACAATTA1-1-3-6-6AtCATtctcaaCAATTA285_3-20,8030601285ATCATTCTCAACAATTA5-6-2-2-2ATCATtctcaaCAatTA285_4-20,4630601285ATCATTCTCAACAATTA4-7-1-1-4ATCAttctcaaCaATTA285_5-19,8030601285ATCATTCTCAACAATTA5-7-1-1-3ATCATtctcaacAaTTA285_6-19,3130601285ATCATTCTCAACAATTA5-6-3-1-2ATCATtctcaaCAAtTA285_7-20,9730601285ATCATTCTCAACAATTA4-7-2-1-3ATCAttctcaaCAaTTA285_8-20,1630601285ATCATTCTCAACAATTA5-6-1 - 1-4ATCATtctcaaCaATTA285_9-21,0530601285ATCATTCTCAACAATTA5-6-1 - 1-1-1-2ATCATtctcaaCaAtTA285_10-19,2930601285ATCATTCTCAACAATTA1-1-3-7-5AtCATtctcaacAATTA285_11-18,7030601286AAGATCATTCTCAACA4-10-2AAGAtcattctcaaCA286_1-17,1530605287TCTCAAAGATCATTCTC3-11-3TCTcaaagatcattCTC287_1-19,0230609288TCTCAAAGATCATTCT4-10-2TCTCaaagatcattCT288_1-17,8130610289ACTTAATTATACTTCC4-10-2ACTTaattatacttCC289_1-17,2830667290TACACTTAATTATACTTC2-12-4TAcacttaattataCTTC290_1-16,8730668291TTACACTTAATTATACTT3-12-3TTAcacttaattataCTT291_1-16,2030669292TTTACACTTAATTATACT2-12-4TTtacacttaatta TACT292_1-16,2330670293CTATTTAATTTACACTT3-11-3CTAtttaatttacaCTT293_1-16,2630679294TATCTATTTAATTTACAC3-12-3TATctatttaatttaCAC294_1-16,0630681295TTTATCTATTTAATTTACA4-13-2TTT AtctatttaatttaCA295_1-16,3430682296CTCTGCTTATAACTTT4-10-2CTCTgcttataactTT296_1-18,5130699297CCTCTGCTTATAACTT3-10-3CCT ctgcttataaCTT297_1-21,2930700298TCCTCTGCTTATAACTT3-12-2TCCtctgcttataacTT298_1-20,8630700299TCCTCTGCTTATAACT3-11-2TCCtctgcttataaCT299_1-20,7030701300TTCCTCTGCTTATAACT3-12-2TTCctctgcttataaCT300_1-20,0330701301TTTCCTCTGCTTATAAC4-11-2TTTCctctgcttataAC301_1-19,2030702302TACTATACTTTCCTCT2-10-4TActatactttcCTCT302_1-20,0730711303TTCTACTATACTTTCC4-10-2TTCTactatactttCC303_1-19,5530714304AGTTCTACTATACTTTC4-11-2AGTTctactatacttTC304_1-18,4930715304AGTTCTACTATACTTTC1-10-6AgttctactatACTTTC304_2-18,7630715304AGTTCTACTATACTTTC1-1-2-7-1-1-4AgTTctactatAcTTTC304_3-18,2330715304AGTTCTACTATACTTTC3-8-2-2-2AGTtctactatACttTC304_4-19,1930715304AGTTCTACTATACTTTC2-2-1-6-1-1-4AGttCtactatAcTTTC304_5-19,0730715304AGTTCTACTATACTTTC1-2-2-8-4AgtTCtactatacTTTC304_6-18,4630715304AGTTCTACTATACTTTC3-10-1-1-2AGTtctactatacTtTC304_7-18,1230715304AGTTCTACTATACTTTC3-11-3AGTtctactatactTTC304_8-18,4230715304AGTTCTACTATACTTTC3-1-1-10-2AGTtCtactatacttTC304_9-18,5830715304AGTTCTACTATACTTTC2-1-2-10-2AGtTCtactatacttTC304_10-18,0230715304AGTTCTACTATACTTTC1-2-2-6-2-1-3AgtTCtactatACtTTC304_11-19,0230715304AGTTCTACTATACTTTC2-1-2-6-1-3-2AGtTCtactatActtTC304_12-18,2230715304AGTTCTACTATACTTTC2-2-1-7-2-1-2AGttCtactataCTtTC304_13-19,2230715304AGTTCTACTATACTTTC3-1-1-7-1-1-3AGTtCtactataCtTTC304_14-20,3930715304AGTTCTACTATACTTTC1-1-1-1-1-8-4AgTtCtactatacTTTC304_15-18,1330715305GTTCTACTATACTTTC4-10-2GTTCtactatacttTC305_1-17,4830715306CATTATATTTAAACTATCA4-13-2CATTatatttaaactatCA306_1-16,9331630307CACATTATATTTAAACTAT2-13-4CAcattatatttaaaCTAT307_1-17,1131632308ACACATTATATTTAAACTA3-13-3ACAcattatatttaaaCTA308_1-17,0931633309ACCACCTAAGACCTCAA2-11-4ACcacctaagaccTCAA309_1-22,4932755310CCACCTAAGACCTCAA2-10-4CCacctaagaccTCAA310_1-22,6332755311ACCACCTAAGACCTCA2-11-3ACcacctaagaccTCA311_1-21,7432756312ACCTTAAGTAACATTT4-10-2ACCTtaagtaacatTT312_1-16,8233366313CACCTTAAGTAACATT4-10-2CACCttaagtaaca TT313_1-18,0533367314CCACCTTAAGTAACAT3-10-3CCAccttaagtaaCAT314_1-20,7033368315ACCACCTTAAGTAACA4-10-2ACCAccttaagtaaCA315_1-20,6833369316TTATTAACCACCTTAA3-10-3TTAttaaccacctTAA316_1-16,1933375317CATTATTAACCACCTT2-10-4CAttattaaccaCCTT317_1-19,9233377318ACATTATTAACCACCT3-10-3ACAttattaaccaCCT318_1-20,1433378319ACCAATTATACTTACAA3-11-3ACCaattatacttaCAA319_1-17,1636606320AACCAATTATACTTACA4-11-2AACCaattatacttaCA320_1-17,1636607321CAAATACAGATTATCC2-10-4CAaatacagattATCC321_1-16,4438092322TTTACATTCCCATCATC2-11-4TTtacattcccatCATC322_1-21,0838297323CACACCTATTATATAAT4-11-2CACAcctattatataAT323_1-17,0239173324TCACACCTATTATATAA3-11-3TCAcacctattataTAA324_1-17,0239174325CTTCACACCTATTATATA2-12-4CTtcacacctattaTATA325_1-20,6539175326ACTTCACACCTATTATAT3-12-3ACTtcacacctattaTAT326_1-20,4639176327GCTCACACTAATTATT2-10-4GCtcacactaatTATT327_1-18,7239228328ATGCTCACACTAATTA4-10-2ATGCtcacactaatTA328_1-19,3839230329AATGCTCACACTAATT4-10-2AATGctcacactaaTT329_1-16,2139231330AAACTGTACACCTACT2-10-4AAactgtacaccTACT330_1-17,9939563331GTTTCCATCTACTATTA2-11-4GTttccatctactATTA331_1-19,7839808332TTTCCATCTACTATTA4-10-2TTTCcatctactatTA332_1-17,2539808333TGACATAACCATATAC3-10-3TGAcataaccataTAC333_1-16,6339931334GCTCCCAAACAACTAA2-12-2GCtcccaaacaactAA334_1-17,5541114335CCTCAATACTCTACTT4-10-2CCTCaatactctacTT335_1-20,3041444336GACCTCAATACTCTACT3-11-3GACctcaatactctACT336_1-21,0141445337GACCTCAATACTCTAC4-10-2GACCtcaatactctAC337_1-20,0241446338TACTAAACATACACATA4-11-2TACTaaacatacacaTA338_1-16,1241725339CTACTAAACATACACAT3-11-3CTActaaacatacaCAT339_1-17,3141726340TTCTACTAAACATACAC3-11-3TTCtactaaacataCAC340_1-16,0741728341TACCAATAGTTACCTT2-10-4TAccaatagttaCCTT341_1-20,0342167342CTTACCAATAGTTACCT3-11-3CTT accaatagttaCCT342_1-22,2942168343TTACCAATAGTTACCT3-10-3TTAccaatagttaCCT343_1-20,0342168344CTTACCAATAGTTACC4-10-2CTT AccaatagttaCC344_1-20,0342169345TCTTACCAATAGTTACC4-11-2TCTTaccaatagttaCC345_1-21,3042169346TCAAAGCACACCACCAC2-12-3TCaaagcacaccacCAC346_1-21,6942287347ATTCAAAGCACACCACC2-12-3A TtcaaagcacaccACC347_1-21,0042289348AGACTAATCCTCTTAA3-10-3AGActaatcctctTAA348_1-17,7243452349TAGACTAATCCTCTTA4-10-2TAGActaatcctctTA349_1-19,2043453350CCCATTTCTAACATTTAC3-12-3CCCatttctaacattTAC350_1-22,9343562351ACCCATTTCTAACATT4-10-2ACCCatttctaaca TT351_1-20,6443565352AACCCATTTCTAACAT4-10-2AACCcatttctaacAT352_1-18,2543566353CCTCAACTTCACCAAT2-10-4CCtcaacttcacCAAT353_1-21,7343634354ACTGATTTCCTTAAAC4-10-2ACTGatttccttaaAC354_1-16,6744180355CACTGATTTCCTTAAAC4-11-2CACTgatttccttaaAC355_1-18,9144180356CCACTGATTTCCTTAAA4-11-2CCACtgatttccttaAA356_1-20,9144181357ACCACTGATTTCCTTA2-10-4ACcactgatttcCTTA357_1-20,9844183358CACCACTGATTTCCTT3-10-3CACcactgatttcCTT358_1-22,0444184359CTCTGCAATACACCAA2-10-4CTctgcaatacaCCAA359_1-20,9044439360ACTCTGCAATACACCA3-10-3ACT ctgcaatacaCCA360_1-22,1944440361TACTCTGCAATACACCA2-11-4TActctgcaatacACCA361_1-22,3244440361TACTCTGCAATACACCA1-1-1-10-1-1-2TaCtctgcaatacAcCA361_2-19,2944440361TACTCTGCAATACACCA1-3-1-8-1-1-2TactCtgcaatacAcCA361_3-19,2844440361TACTCTGCAATACACCA1-10-1-3-2TactctgcaatAcacCA361_4-18,3544440361TACTCTGCAATACACCA2-10-2-1-2TActctgcaataCAcCA361_5-21,6344440361TACTCTGCAATACACCA1-13-3TactctgcaatacaCCA361_6-20,5444440361TACTCTGCAATACACCA2-10-1-2-2TActctgcaataCacCA361_7-20,0644440361TACTCTGCAATACACCA1-1-1-12-2TaCtctgcaatacacCA361_8-19,1444440361TACTCTGCAATACACCA1-2-2-10-2TacTCtgcaatacacCA361_9-20,3344440361TACTCTGCAATACACCA1-3-1-10-2TactCtgcaatacacCA361_10-19,1344440362TACTCTGCAATACACC2-10-4TActctgcaataCACC362_1-21,1244441362TACTCTGCAATACACC1-1-1-11-2TaCtctgcaatacaCC362_2-18,2344441362TACTCTGCAATACACC1-1-1-10-3TaCtctgcaatacACC362_3-18,7844441362TACTCTGCAATACACC1-3-1-7-4TactCtgcaataCACC362_4-20,8744441362TACTCTGCAATACACC3-11-2TACtctgcaatacaCC362_5-19,8644441362TACTCTGCAATACACC2-2-1-9-2TActCtgcaatacaCC362_6-19,4444441362TACTCTGCAATACACC2-12-2TActctgcaatacaCC362_7-18,4744441362TACTCTGCAATACACC1-2-2-9-2TacTCtgcaatacaCC362_8-19,4244441362TACTCTGCAATACACC2-1-2-9-2TAcTCtgcaatacaCC362_9-20,6444441362TACTCTGCAATACACC1-3-1-9-2TactCtgcaatacaCC362_10-18,2244441363TTACTCTGCAATACACC2-11-4TTactctgcaataCACC363_1-21,7144441364TTACTCTGCAATACAC3-10-3TTActctgcaataCAC364_1-17,7544442365TTTACTCTGCAATACAC3-11-3TTT actctgcaataCAC365_1-18,3444442366CTTTACTCTGCAATACA2-11-4CTttactctgcaaTACA366_1-20,2344443367TTTACTCTGCAATACA2-10-4TTtactctgcaaTACA367_1-17,5644443368GACCACACTTTCTACCA2-13-2GAccacactttctacCA368_1-21,7244477369GACCACACTTTCTACC2-12-2GAccacactttctaCC369_1-20,8144478370AAGAAACACCCTTCCA2-10-4AAgaaacaccctTCCA370_1-21,4844776371ATCTGCTACATATTCTT4-11-2ATCTgctacatattcTT371_1-19,8845216372ATCTGCTACATATTCT4-10-2ATCTgctacatattCT372_1-19,7145217373CATCTGCTACATATTCT4-11-2CATCtgctacatattCT373_1-21,3245217374CATCTGCTACATATTC4-10-2CATCtgctacatatTC374_1-18,8245218375TTCAACCCTAATCACT4-10-2TTCAaccctaatcaCT375_1-19,9945246376ATTCAACCCTAATCAC2-10-4ATtcaaccctaaTCAC376_1-18,6745247377CATTCAACCCTAATCA3-10-3CATtcaaccctaaTCA377_1-19,9345248378GCATTCAACCCTAATCA3-12-2GCAttcaaccctaatCA378_1-22,5645248379AGCATTCAACCCTAATC4-11-2AGCAttcaaccctaaTC379_1-22,9845249380GCATTCAACCCTAATC4-10-2GCATtcaaccctaaTC380_1-21,6345249381AGCATTCAACCCTAAT4-10-2AGCAttcaaccctaAT381_1-21,6245250382CAGCATTCAACCCTAAT3-12-2CAGcattcaaccctaAT382_1-21,1245250383TTAAATCCAGCATTCA3-10-3TTAaatccagcatTCA383_1-18,0845258384CTCCATATTTAAATCC4-10-2CTCCatatttaaatCC384_1-20,0245266385GCTCCATATTTAAATCC4-11-2GCTCcatatttaaatCC385_1-22,8445266386GCTCCATATTTAAATC4-10-2GCTCcatatttaaa TC386_1-18,7845267387AGCTCCATATTTAAAT4-10-2AGCTccatatttaaAT387_1-18,6245268388TAAGCTCCATATTTAA3-10-3TAAgctccatattTAA388_1-16,0845270389CCTAAGCTCCATATTTA3-11-3CCTaagctccatatTTA389_1-22,6545271390CTAAGCTCCATATTTA4-10-2CTAAgctccatattTA390_1-18,8145271391CCTAAGCTCCATATTT4-10-2CCT AagctccatatTT391_1-21,5745272392TCTACCCTAAATTCCC2-11-3TCtaccctaaattCCC392_1-23,0045560393CACATCTTGTATACAA3-10-3CACatcttgtataCAA393_1-16,6545627394ACACATCTTGTATACA4-10-2ACACatcttgtataCA394_1-17,9545628395CTACACATCTTGTATAC3-11-3CTAcacatcttgtaTAC395_1-19,1345629396TACACATCTTGTATAC3-10-3TACacatcttgtaTAC396_1-16,7345629397CTTGACTACACATCTT3-10-3CTTgactacacatCTT397_1-18,8945635398CTCTACAACAGTCCCA3-11-2CTCtacaacagtccCA398_1-22,0645709399TCTCTACAACAGTCCCA2-13-2TCtctacaacagtccCA399_1-21,7045709400ATAACATTACTCTTAACA3-12-3AT AacattactcttaACA400_1-17,0346215401TTTGACATTCCATCTCC2-12-3TTtgacattccatcTCC401_1-21,6246256402CTTTGACATTCCATCTC2-11-4CTttgacattcca TCTC402_1-21,8846257403TCTTTGACATTCCATCTC4-12-2TCTTtgacattccatcTC403_1-22,4146257404TTTGACATTCCATCTC3-10-3TTT gacattccatCTC404_1-19,4046257405ATCTTTGACATTCCATC2-11-4AT ctttg acattcC AT C405_1-20,5346259406TATCTTTGACATTCCAT2-11-4TAtctttgacattCCAT406_1-21,3246260407TACTATCTTTGACATTC4-11-2TACT atctttgacatTC407_1-18,3946263408TACTATCTTTGACATT4-10-2TACT atctttgaca TT408_1-16,8446264409CTGTATACACCATCCC2-12-2CTgtatacaccatcCC409_1-21,8446392410TCTGTATACACCATCC4-10-2TCTGtatacaccatCC410_1-22,7346393411TTTCTGACTCCCTATCC2-13-2TTtctgactccctatCC411_1-22,4846420412CCTATGTTAATACTTTC4-11-2CCT AtgttaatacttTC412_1-19,5346505413CTATGTTAATACTTTC4-10-2CTATgttaatacttTC413_1-16,0946505414CCTATGTTAATACTTT4-10-2CCT AtgttaatactTT414_1-17,8546506415TCCTATGTTAATACTT3-10-3TCCtatgttaataCTT415_1-18,4746507416ATCCTATGTTAATACT4-10-2A TCCtatgttaataCT416_1-18,7146508417ATTTCATTAAGTCACCC3-11-3A TTtcattaagtcaCCC417_1-22,1647364418ATTTCATTAAGTCACC2-10-4A TttcattaagtCACC418_1-18,7947365419CTCTCCTCAAGATCAAC3-11-3CTCtcctcaagatcAAC419_1-20,2948110420CTCTCCTCAAGATCAA3-10-3CTCtcctcaagatCAA420_1-20,3348111421CCATACAGTATATACA4-10-2CCATacagtatataCA421_1-19,5348186422CAACTATTATCTTCTT2-10-4CAactattatctTCTT422_1-16,3848221423ACAACTATTATCTTCT3-10-3ACAactattatctTCT423_1-16,6048222424TTGCTTCCAATTTATTT4-11-2TTGCttccaatttatTT424_1-19,9350282425ATCTCATGACCACCTAA3-11-3ATCtcatgaccaccTAA425_1-21,7451241425ATCTCATGACCACCTAA1-1-1-9-2-1-2AtCtcatgaccaCCtAA425_2-21,1151241425ATCTCATGACCACCTAA1-1-1-8-1-2-3AtCtcatgaccAccTAA425_3-19,9651241425ATCTCATGACCACCTAA1-12-4AtctcatgaccacCTAA425_4-20,4051241425ATCTCATGACCACCTAA3-10-1-1-2ATCtcatgaccacCtAA425_5-20,6651241425ATCTCATGACCACCTAA1-1-1-10-1-1-2AtCtcatgaccacCtAA425_6-18,7251241425ATCTCATGACCACCTAA1-1-1-9-1-1-3AtCtcatgaccaCcTAA425_7-20,5951241425ATCTCATGACCACCTAA1-2-2-7-1-1-3AtcTCatgaccaCcTAA425_8-21,4851241425ATCTCATGACCACCTAA1-3-1-8-4AtctCatgaccacCTAA425_9-21,0751241425ATCTCATGACCACCTAA1-1-3-8-1-1-2AtCTCatgaccacCtAA425_10-21,2751241426TCTCATGACCACCTAA2-10-4TCtcatgaccacCTAA426_1-21,2551241427ATCTCATGACCACCTA3-10-3ATCtcatgaccacCTA427_1-22,5651242428TATCTCATGACCACCTA2-12-3TAtctcatgaccacCTA428_1-21,8851242429TTTATCTCATGACCACC2-11-4TTtatctcatgacCACC429_1-22,3751244430TTTATCTCATGACCAC2-10-4TTtatctcatgaCCAC430_1-19,5651245431ATTCTTACCGTCTTTA4-10-2ATTCttaccgtcttTA431_1-19,5251358432TATTCTTACCGTCTTTA3-11-3TATtcttaccgtctTTA432_1-20,1051358433TATTCTTACCGTCTTT2-10-4TAttcttaccgtCTTT433_1-19,3051359434TTATTCTTACCGTCTTT2-11-4TTattcttaccgtCTTT434_1-19,9951359435ATCTGATCTCACACAT3-10-3ATCtgatctcacaCAT435_1-19,6251438436CATCTGATCTCACACAT4-11-2CATCtgatctcacacAT436_1-20,8251438437ACTTCCAGATTTCTACA2-11-4ACttccagatttcTACA437_1-21,4451953438TTTATGTTTACTTCAT3-10-3TTTatgtttacttCAT438_1-16,0552150439TAAAGATCCCATCACTC3-11-3TAAagatcccatcaCTC439_1-20,3152549440TAAAGATCCCATCACT4-10-2TAAAgatcccatcaCT440_1-18,8252550441CCTAAAGATCCCATCAC2-12-3CCtaaagatcccatCAC441_1-22,3252551442ATCATCAGTTACATCA4-10-2ATCAtcagttacatCA442_1-18,6452579443ACTCTCACTGTAACTTT4-11-2ACTCtcactgtaactTT443_1-19,7653012444AACTCTCACTGTAACTT3-11-3AACtctcactgtaaCTT444_1-18,5353013445ACTCTCACTGTAACTT3-10-3ACT ctcactgtaaCTT445_1-19,0453013446AACTCTCACTGTAACT4-10-2AACTctcactgtaaCT446_1-17,9753014447CAACTCTCACTGTAACT4-11-2CAACtctcactgtaaCT447_1-20,0153014448CCTTTCATTAACATTTA3-11-3CCTttcattaacatTTA448_1-19,0354198449TTCCTTTCATTAACATTT4-12-2TTCCtttcattaacatTT449_1-19,9254199450TAATCCTATTCCAACT3-10-3TAAtcctattccaACT450_1-18,0554232451CTAATCCTATTCCAAC2-10-4CTaatcctattcCAAC451_1-18,6554233452CTCTAATCCTATTCCA3-10-3CTCtaatcctattCCA452_1-22,5854235453TCTCTAATCCTATTCC4-10-2TCTCtaatcctattCC453_1-21,7854236454TTGTCTCTAATCCTATT2-11-4TTgtctctaatccTATT454_1-19,7054238455TTGTCTCTAATCCTAT2-10-4TTgtctctaatcCTAT455_1-19,4554239456TCTTTAAGCTTCCCAC2-10-4TCtttaagcttcCCAC456_1-22,9654609457AAACTACCCTGCACAA3-10-3AAActaccctgcaCAA457_1-18,4154924458CCATGCTACATAAACC4-10-2CCATgctacataaaCC458_1-22,2555337459TCCATGCTACATAAAC4-10-2TCCAtgctacataaAC459_1-18,6455338460ACTCCTAAGAATTACA4-10-2ACTCctaagaattaCA460_1-17,6259565461GAAACTATTACTCCTA2-10-4GAaactattactCCTA461_1-19,0659574462TGAAACTATTACTCCT3-10-3TGAaactattactCCT462_1-19,3059575463ATGAAACTATTACTCC2-10-4ATgaaactattaCTCC463_1-17,9659576464AACAACTCATGCCACA2-10-4AAcaactcatgcCACA464_1-19,7260012465AAATATTGCCACCATT2-10-4AAatattgccacCATT465_1-17,7860298466GTTACATATTCTTTCAC3-11-3GTTacatattctttCAC466_1-18,7660448467TCATACTTGCTTTAAT4-10-2TCATacttgctttaAT467_1-17,2960821468ATCCTGATAATTAACT4-10-2ATCCtgataattaaCT468_1-17,7361925469CCTTAATCTGTATCAC3-10-3CCTtaatctgtatCAC469_1-19,9262287470ATACACAGCACATATT2-10-4ATacacagcacaTATT470_1-17,5862422471TCAGAATAATTCTCCT3-10-3TCAgaataattctCCT471_1-19,8162443472TCTTCAGCTTTCTAAAT4-11-2TCTTcagctttctaaAT472_1-18,5864113473AGTCCTTCCTTTAACCA2-13-2AGtccttcctttaacCA473_1-22,2064461474TAGTCCTTCCTTTAACC2-13-2TAgtccttcctttaaCC474_1-22,1264462475TTTAACCTTGCTTATA2-10-4TTtaaccttgctTATA475_1-17,5065272476ATCCCTTTGTAATCAT4-10-2ATCCctttgtaatcAT476_1-20,3166840477CTTGCATTTCTAATTAC3-11-3CTTgcatttctaatTAC477_1-18,0967426478CTTGTCAAATCATTTCT4-11-2CTTGtcaaatcatttCT478_1-19,1068194479CCATCTAATGATTATT4-10-2CCATctaatgattaTT479_1-17,2868328480TATCAGTTATCCAATA4-10-2TATCagttatccaaTA480_1-17,3968805481TCACTGCCATCAATAC4-10-2TCACtgccatcaatAC481_1-19,7168921482TGTCATCTACAAATCA4-10-2TGTCatctacaaatCA482_1-18,0170133483CTCTTTAGATTCATCC4-10-2CTCTttagattcatCC483_1-20,9472377484ACTCTTTAGATTCATC2-10-4ACtctttagattCATC484_1-17,8172378485CAACTCTATGACTACC2-10-4CAactctatgacTACC485_1-20,0772826486ACCTGTAATACTTCTT4-10-2ACCTgtaatacttcTT486_1-19,6772861487GAATTCTTTATTCCTCC2-11-4GAattctttattcCTCC487_1-22,5372887488ATCTGAATCAAACCTT2-10-4AT ctgaatcaaaCCTT488_1-17,9773474489ACTTTACTGCCATAATC3-11-3ACTttactgccataATC489_1-19,6073992490TTACTCTTAGCAACCT4-10-2TTACtcttagcaacCT490_1-20,1974791491CACCAGTATTTCTTCTT4-11-2CACCagtatttcttcTT491_1-22,1574851492TTCACCAGTATTTCTTC4-11-2TTCAccagtatttctTC492_1-20,4374853493CCAAATAAGCAAACTC3-10-3CCAaataagcaaaCTC493_1-17,5475840494CCCAAATAAGCAAACT4-10-2CCCAaataagcaaaCT494_1-20,2375841495GACTACATTCTCAATA3-10-3GACtacattctcaATA495_1-17,4976238496TTGTCAATCTTTATTCT4-11-2TTGTcaatctttattCT496_1-18,8576254497AGCTTACCAAATATTC4-10-2AGCTtaccaaatatTC497_1-18,6876811498TTACACATGTATATCC3-10-3TTAcacatgtataTCC498_1-18,2377114499ATCCTGTTAATACCAT2-10-4ATcctgttaataCCAT499_1-20,4180468500TTCTTAGTCACACACA4-10-2TTCTtagtcacacaCA500_1-19,3781047501TTCTGTTTCCATTTACA4-11-2TTCTgtttccatttaCA501_1-21,3182233502TCTATATCAAGTTCCTT2-11-4TCtatatcaagttCCTT502_1-20,9584166503ATTCAGTTACCAACTA3-10-3ATTcagttaccaaCTA503_1-18,3785392504GCTTCTACTTAAATAT3-10-3GCTtctacttaaaTAT504_1-17,5886974505CCCTCAAAGTAATTTC4-10-2CCCTcaaagtaattTC505_1-20,5387728506AACATGTAATTTCCAT2-10-4AAcatgtaatttCCAT506_1-17,2187810507CCAGACTCCAATATTT4-10-2CCAGactccaatatTT507_1-20,7888417508CTTAGACTTCACCTTTC2-11-4CTtagacttcaccTTTC508_1-20,5688991509CTGCTTAATTATATCA4-10-2CTGCttaattatatCA509_1-18,8590228510AAATTGTCTACCTTCCT2-12-3AAattgtctaccttCCT510_1-20,6290474511CACTTAGAATATCCCT2-10-4CActtagaatatCCCT511_1-22,2891625512ATCCAAAGTTTCTTTC4-10-2ATCCaaagtttcttTC512_1-18,6491885513ATATTTGTCACCTAAC4-10-2ATATttgtcacctaAC513_1-17,1292976514CTATTCTCAGTATTAT3-10-3CTAttctcagtatTAT514_1-17,4294304515CCATTCAATGATCACT2-10-4CCattcaatgatCACT515_1-20,5594528516CACTAGTACTCTTATT4-10-2CACTagtactcttaTT516_1-18,0195653517GCCACAACATCTATTT4-10-2GCCAcaacatctatTT517_1-21,5396751518AGCACATATACCATCA4-10-2AGCAcatataccatCA518_1-21,9897636519GTCATCTAACTTCTTAC3-11-3GTCatctaacttctTAC519_1-19,2598480520TGTCATCTAACTTCTTA4-11-2TGTCatctaacttctTA520_1-19,6998481521CCCTTATAGTTATTAA3-10-3CCCttatagttatTAA521_1-19,3299646522TCCATAGAATTCTTCA4-10-2TCCAtagaattcttCA522_1-19,92100334523TTGATTCCACCATTAA3-10-3TTGattccaccatTAA523_1-18,05101110524CAGCCATAAACTATAT4-10-2CAGCcataaactatAT524_1-18,60101898525TATGACTTATTCCATA2-10-4TAtgacttattcCATA525_1-17,88102558526GTTAACCTATATTTCA4-10-2GTT AacctatatttCA526_1-17,69103589527TGTCTATTCTCTTCATT4-11-2TGTCtattctcttcaTT527_1-20,62104309528TTACTCTTTGATTTCAT3-11-3TTActctttgatttCAT528_1-18,39105686529GATAATTCCAAATCCC2-10-4GAtaattccaaaTCCC529_1-20,99107972530TCTTATCCTTGAATTTC4-11-2TCTTatccttgaattTC530_1-18,85108257531ATATCCCTTGATTATCC3-11-3ATAtcccttgattaTCC531_1-22,75109407532TTAGTATACCCTTTAT3-10-3TTAgtatacccttTAT532_1-18,67110210533CTCTTTGTCAAATACT4-10-2CTCTttgtcaaataCT533_1-18,16110768534CCAAACTGTCTTCTAAT2-11-4CCaaactgtcttcTAAT534_1-19,87111811535TCCAAACTGTCTTCTAA3-12-2TCCaaactgtcttctAA535_1-18,33111812536CCAGCATATTATATAC3-10-3CCAgcatattataTAC536_1-18,96112149537TCCAGCATATTATATA4-10-2TCCAgcatattataTA537_1-19,41112150538TCATTGAACAACTCTTC4-11-2TCATtgaacaactctTC538_1-18,01112945539CTGCCATCTTTATTTAT4-11-2CTGCcatctttatttAT539_1-21,89113533540TGAAACATTCTTCCCAC2-12-3TGaaacattcttccCAC540_1-19,76114274541TTTATTAGATTACTCC2-10-4TTtattagattaCTCC541_1-17,38114495542TTCCAGCTTATTTACCT3-12-2TTCcagcttatttacCT542_1-21,28114831543AGCATCATATAAACCT3-10-3AGCatcatataaaCCT543_1-20,62115355544GTACTTACACATCTAT2-10-4GTacttacacatCTAT544_1-18,96116105545TGTACTTACACATCTA3-10-3TGTacttacacatCTA545_1-19,38116106546ATTTCTCTATGTCACAT3-11-3ATTtctctatgtcaCAT546_1-19,28117096547CAAACCTACGTCTCTC2-10-4CAaacctacgtcTCTC547_1-20,87117189548GTATTTACTCTTTACCT3-11-3GTAtttactctttaCCT548_1-22,15117476549CTAATGCAATAACCCA2-10-4CTaatgcaataaCCCA549_1-21,79118293550ACTAATGCAATAACCC3-10-3ACT aatgcaataaCCC550_1-20,53118294551AGCTCTAAACCTTCAA3-10-3AGCtctaaaccttCAA551_1-20,51118756552TATTTGTCACCAAACC3-10-3TATttgtcaccaaACC552_1-19,63119621553CTCAGACATCTCAATA4-10-2CTCAgacatctcaaTA553_1-19,25120655554TCTCAGCTTCTTCAAAT2-12-3TCtcagcttcttcaAAT554_1-18,33123733555GCCAATACCCACAAAC3-10-3GCCaatacccacaAAC555_1-22,03124163556CCTCTGACAACCATTA4-10-2CCTCtgacaaccatTA556_1-22,57125512557CAGATAACTCTAAACC4-10-2CAGAtaactctaaaCC557_1-18,43126882558CTAACTGTTTCTCAATT3-11-3CTAactgtttctcaATT558_1-18,10127105559CCAAGATAATCATCAT3-10-3CCAagataatcatCAT559_1-18,37127809560TACATATTGTACTTCT4-10-2TACAtattgtacttCT560_1-17,48129020561TAGCCTACTTTAATAT4-10-2TAGCctactttaatAT561_1-18,67129205562CATTTACAAGCACATA2-10-4CAtttacaagcaCATA562_1-17,81129928563TTATTCTGACACACTT3-10-3TTAttctgacacaCTT563_1-17,49130020564TACATTGACACCTAAT4-10-2TACAttgacacctaAT564_1-17,37130884565TTTACATTGACACCTA2-10-4TTtacattgacaCCTA565_1-19,42130886566TGTATATAACTATTCC4-10-2TGTAtataactattCC566_1-17,79131404567GAATCTTCTAATTCCAC2-11-4GAatcttctaattCCAC567_1-20,40132514568TGCTCACTAACTACAC3-10-3TGCtcactaactaCAC568_1-20,66133367569TGCTACCATCATTACCT2-13-2TGctaccatcattacCT569_1-21,32136198570TTTATCAATATCTTCTCACT1-13-1-1-1-1-2TttatcaatatcttCtCaCT570_1-19,695784570TTTATCAATATCTTCTCACT1-2-1-10-1-2-3TttAtcaatatcttCtcACT570_2-19,675784570TTTATCAATATCTTCTCACT1-5-1-7-1-2-3TttatcAatatcttCtcACT570_3-19,655784570TTTATCAATATCTTCTCACT1-1-1-11-1-3-2TtTatcaatatcttCtcaCT570_4-19,755784570TTTATCAATATCTTCTCACT1-2-1-2-1-11-2TttAtcAatatcttctcaCT570_5-18,215784570TTTATCAATATCTTCTCACT1-4-1-8-1-3-2TttatCaatatcttCtcaCT570_6-19,695784570TTTATCAATATCTTCTCACT1-2-1-2-1-9-1-1-2TttAtcAatatcttctCaCT570_7-18,885784570TTTATCAATATCTTCTCACT1-2-1-1-1-11-3TttAtCaatatcttctcACT570_8-19,365784570TTTATCAATATCTTCTCACT1-4-1-10-1-1-2TttatCaatatcttctCaCT570_9-19,385784570TTTATCAATATCTTCTCACT2-1-1-10-1-1-1-1-2TTtAtcaatatcttCtCaCT570_10-20,605784570TTTATCAATATCTTCTCACT1-4-1-8-1-1-1-1-2TttatCaatatcttCtCaCT570_11-20,365784570TTTATCAATATCTTCTCACT1-2-1-1-1-8-1-2-3TttAtCaatatcttCtcACT570_12-20,345784570TTTATCAATATCTTCTCACT1-2-1-2-1-7-1-3-2T ttAtcAatatcttCtcaC T570_13-19,195784570TTTATCAATATCTTCTCACT1-1-2-1-1-10-1-1-2TtT AtCaatatcttctCaCT570_14-21,245784571TTTATCAATATCTTCTCAC1-12-2-1-3TttatcaatatctTCtCAC571_1-19,165785571TTTATCAATATCTTCTCAC2-1-1-1-1-6-2-2-3TTtAtCaatatcTTctCAC571_2-20,175785571TTTATCAATATCTTCTCAC3-2-1-7-2-2-2TTT atCaatatctT CtcAC571_3-19,795785571TTTATCAATATCTTCTCAC1-2-3-8-1-2-2TttA TCaatatcttCtcAC571_4-18,785785571TTTATCAATATCTTCTCAC1-4-1-9-4TttatCaatatcttcTCAC571_5-19,065785571TTTATCAATATCTTCTCAC2-1-1-1-1-8-1-1-3TTtAtCaatatcttCtCAC571_6-19,755785571TTTATCAATATCTTCTCAC1-1-1-2-1-6-1-3-3TtTatCaatatcTtctCAC571_7-19,115785571TTTATCAATATCTTCTCAC2-1-3-6-1-4-2TTtATCaatatcTtctcAC571_8-19,135785571TTTATCAATATCTTCTCAC4-12-3TTT AtcaatatcttctCAC571_9-20,385785571TTTATCAATATCTTCTCAC1-1-2-1-1-6-1-3-3TtT AtCaatatcTtctCAC571_10-20,245785571TTTATCAATATCTTCTCAC2-1-1-1-1-7-2-2-2TTtAtCaatatctTCtcAC571_11-18,655785571TTTATCAATATCTTCTCAC3-2-1-8-1-1-3TTT atCaatatcttCtCAC571_12-20,895785571TTTATCAATATCTTCTCAC1-3-2-8-1-1-3Ttta TCaatatcttCtCAC571_13-19,965785571TTTATCAATATCTTCTCAC1-2-1-1-1-9-4TttAtCaatatcttcTCAC571_14-19,165785572TTTATCAATATCTTCTCA2-1-1-1-1-7-2-1-2TTtAtCaatatctTCtCA572_1-18,695786572TTTATCAATATCTTCTCA3-2-1-6-1-1-1-1-2TTTatCaatatcTtCtCA572_2-19,365786572TTTATCAATATCTTCTCA1-4-1-6-1-1-4TttatCaatatcTtCTCA572_3-19,195786572TTTATCAATATCTTCTCA1-2-3-6-1-2-3TttATCaatatcTtcTCA572_4-19,565786572TTTATCAATATCTTCTCA4-1-1-7-1-2-2TTTAtCaatatctTctCA572_5-19,375786572TTTATCAATATCTTCTCA1-2-3-8-1-1-2TttATCaatatcttCtCA572_6-18,835786572TTTATCAATATCTTCTCA3-2-1-9-3TTTatCaatatcttcTCA572_7-19,075786572TTTATCAATATCTTCTCA1-2-1-10-4TttAtcaatatcttCTCA572_8-18,105786572TTTATCAATATCTTCTCA4-10-1-1-2TTT AtcaatatcttCtCA572_9-19,315786572TTTATCAATATCTTCTCA2-1-3-6-1-1-1-1-2TTtATCaatatcTtCtCA572_10-20,155786572TTTATCAATATCTTCTCA3-2-1-6-1-2-3TTTatCaatatcTtcTCA572_11-19,595786572TTTATCAATATCTTCTCA1-1-2-1-1-7-2-1-2TtTAtCaatatctTCtCA572_12-19,645786572TTTATCAATATCTTCTCA4-9-1-1-3TTTAtcaatatctTcTCA572_13-19,905786572TTTATCAATATCTTCTCA1-3-2-8-4TttaTCaatatcttCTCA572_14-19,805786573TATACCTTTCTTTAACCCTT1-4-1-10-1-1-2TatacCtttctttaacCcTT573_1-22,728116573TATACCTTTCTTTAACCCTT2-4-1-11-2TAtaccTttctttaacccTT573_2-22,808116573TATACCTTTCTTTAACCCTT1-3-1-10-1-2-2TataCctttctttaaCccTT573_3-22,728116573TATACCTTTCTTTAACCCTT1-4-1-9-1-2-2TatacCtttctttaaCccTT573_4-22,828116573TATACCTTTCTTTAACCCTT1-5-1-9-1-1-2TataccTttctttaacCcTT573_5-22,358116573TATACCTTTCTTTAACCCTT1-15-1-1-2TatacctttctttaacCcTT573_6-21,838116573TATACCTTTCTTTAACCCTT1-2-1-1-1-10-1-1-2TatAcCtttctttaacCcTT573_7-22,918116573TATACCTTTCTTTAACCCTT2-2-1-1-1-11-2TAtaCcTttctttaacccTT573_8-23,588116573TATACCTTTCTTTAACCCTT2-3-1-12-2TAtacCtttctttaacccTT573_9-23,178116573TATACCTTTCTTTAACCCTT1-3-1-8-2-1-1-1-2TataCctttctttAAcCcTT573_10-23,358116573TATACCTTTCTTTAACCCTT2-2-1-1-1-7-1-1-1-1-2TAtaCcTttctttaAcCcTT573_11-24,688116573TATACCTTTCTTTAACCCTT2-4-1-8-2-1-2TAtaccTttctttaaCCcTT573_12-25,868116573TATACCTTTCTTTAACCCTT2-3-1-9-1-2-2TAtacCtttctttaaCccTT573_13-23,968116573TATACCTTTCTTTAACCCTT2-3-1-10-1-1-2TAtacCtttctttaacCcTT573_14-23,858116574TTATACCTTTCTTTAACCCT1-1-1-10-1-4-2TtAtacctttcttTaaccCT574_1-22,318117574TTATACCTTTCTTTAACCCT1-13-1-1-1-1-2TtatacctttctttAaCcCT574_2-22,388117574TTATACCTTTCTTTAACCCT1-1-1-3-1-11-2TtAtacCtttctttaaccCT574_3-22,478117574TTATACCTTTCTTTAACCCT1-3-1-1-1-7-1-3-2TtatAcCtttctttAaccCT574_4-22,688117574TTATACCTTTCTTTAACCCT1-4-1-8-1-3-2TtataCctttctttAaccCT574_5-22,388117574TTATACCTTTCTTTAACCCT1-1-1-13-1-1-2TtAtacctttctttaaCcCT574_6-22,368117574TTATACCTTTCTTTAACCCT1-3-1-11-1-1-2TtatAcctttctttaaCcCT574_7-22,468117574TTATACCTTTCTTTAACCCT1-1-1-2-1-12-2TtAtaCctttctttaaccCT574_8-22,368117574TTATACCTTTCTTTAACCCT1-5-1-11-2TtatacCtttctttaaccCT574_9-22,378117574TTATACCTTTCTTTAACCCT1-1-1-2-1-10-1-1-2TtAtaCctttctttaaCcCT574_10-23,148117574TTATACCTTTCTTTAACCCT1-1-1-3-1-9-1-1-2TtAtacCtttctttaaCcCT574_11-23,258117574TTATACCTTTCTTTAACCCT1-1-1-3-1-10-3TtAtacCtttctttaacCCT574_12-24,758117574TTATACCTTTCTTTAACCCT1-1-1-2-2-11-2TtAtaCCtttctttaaccCT574_13-24,858117574TTATACCTTTCTTTAACCCT1-3-1-1-1-11-2TtatAcCtttctttaaccCT574_14-22,568117575TTTATACCTTTCTTTAACCC1-2-1-9-1-4-2TttAtacctttctTtaacCC575_1-21,698118575TTTATACCTTTCTTTAACCC1-12-1-4-2TttatacctttctTtaacCC575_2-21,598118575TTTATACCTTTCTTTAACCC1-12-1-1-1-2-2TttatacctttctTtAacCC575_3-21,718118575TTTATACCTTTCTTTAACCC1-4-1-10-1-1-2TttatAcctttctttaAcCC575_4-21,908118575TTTATACCTTTCTTTAACCC1-13-1-3-2TttatacctttcttTaacCC575_5-22,018118575TTTATACCTTTCTTTAACCC2-1-1-14-2TTtAtacctttctttaacCC575_6-22,208118575TTTATACCTTTCTTTAACCC1-14-2-1-2TttatacctttctttAAcCC575_7-22,028118575TTTATACCTTTCTTTAACCC1-14-1-2-2TttatacctttctttAacCC575_8-21,418118575TTTATACCTTTCTTTAACCC1-15-1-1-2TttatacctttctttaAcCC575_9-21,718118575TTTATACCTTTCTTTAACCC2-1-1-9-1-4-2TTtAtacctttctTtaacCC575_10-22,508118575TTTATACCTTTCTTTAACCC1-2-1-10-1-3-2TttAtacctttcttTaacCC575_11-22,118118575TTTATACCTTTCTTTAACCC1-4-2-8-2-1-2TttatACctttctttAAcCC575_12-23,408118575TTTATACCTTTCTTTAACCC1-2-1-2-1-9-1-1-2TttAtaCctttctttaAcCC575_13-22,598118575TTTATACCTTTCTTTAACCC1-1-2-14-2TtT AtacctttctttaacCC575_14-23,158118576TTTTATACCTTTCTTTAACC1-1-1-10-2-3-2TtTtatacctttcTTtaaCC576_1-21,128119576TTTTATACCTTTCTTTAACC1-3-1-8-1-4-2TtttAtacctttcTttaaCC576_2-20,108119576TTTTATACCTTTCTTTAACC1-1-1-10-1-2-4TtTtatacctttcTttAACC576_3-21,458119576TTTTATACCTTTCTTTAACC3-11-1-1-1-1-2TTTtatacctttctTtAaCC576_4-21,548119576TTTTATACCTTTCTTTAACC2-4-1-7-1-3-2TTttatAcctttctTtaaCC576_5-20,808119576TTTTATACCTTTCTTTAACC1-14-1-2-2TtttatacctttcttTaaCC576_6-20,228119576TTTTATACCTTTCTTTAACC1-15-1-1-2TtttatacctttctttAaCC576_7-19,618119576TTTTATACCTTTCTTTAACC1-5-1-10-3TtttatAcctttctttaACC576_8-20,518119576TTTTATACCTTTCTTTAACC1-1-2-14-2TtTT atacctttctttaaCC576_9-21,038119576TTTTATACCTTTCTTTAACC1-1-2-10-1-1-1-1-2TtTTatacctttctTtAaCC576_10-21,468119576TTTTATACCTTTCTTTAACC2-2-1-9-1-3-2TTttAtacctttctTtaaCC576_11-20,708119576TTTTATACCTTTCTTTAACC1-5-1-7-1-3-2TtttatAcctttctTtaaCC576_12-19,998119576TTTTATACCTTTCTTTAACC1-1-1-12-2-1-2TtTtatacctttcttTAaCC576_13-21,688119576TTTTATACCTTTCTTTAACC1-1-1-1-1-13-2TtTtAtacctttctttaaCC576_14-19,898119577TTTTTATACCTTTCTTTAAC1-12-1-2-4TttttatacctttCttTAAC577_1-19,198120577TTTTTATACCTTTCTTTAAC1-2-1-9-1-1-2-1-2TttTtatacctttCtTTaAC577_2-18,968120577TTTTTATACCTTTCTTTAAC2-12-3-1-2TTtttatacctttcTTTaAC577_3-19,528120577TTTTTATACCTTTCTTTAAC1-1-1-2-1-7-2-3-2TtTttAtacctttCTttaAC577_4-18,718120577TTTTTATACCTTTCTTTAAC4-9-1-1-1-2-2TTTTtatacctttCtTtaAC577_5-19,858120577TTTTTATACCTTTCTTTAAC3-1-1-8-1-1-1-1-3TTTtTatacctttCtTtAAC577_6-20,088120577TTTTTATACCTTTCTTTAAC2-1-2-8-2-2-3TTtTTatacctttCTttAAC577_7-20,978120577TTTTTATACCTTTCTTTAAC1-1-2-10-2-1-3TtTTtatacctttcTTtAAC577_8-18,898120577TTTTTATACCTTTCTTTAAC1-3-2-7-1-4-2TtttTAtacctttCtttaAC577_9-18,978120577TTTTTATACCTTTCTTTAAC1-2-1-9-2-1-1-1-2TttTtatacctttCTtTaAC577_10-19,348120577TTTTTATACCTTTCTTTAAC2-3-1-7-2-2-3TTtttAtacctttC TttAAC577_11-19,538120577TTTTTATACCTTTCTTTAAC1-1-2-9-1-1-1-1-3TtTTtatacctttCtTtAAC577_12-18,848120577TTTTTATACCTTTCTTTAAC1-3-2-7-1-1-1-2-2TtttTAtacctttCtTtaAC577_13-19,278120577TTTTTATACCTTTCTTTAAC3-1-1-8-1-2-1-1-2TTTtTatacctttCttTaAC577_14-20,208120578TTTTTTCTTACTATCTTCAA1-5-1-7-2-2-2TtttttCttactatCTtcAA578_1-19,028584578TTTTTTCTTACTATCTTCAA2-2-1-1-1-7-1-1-1-1-2TTttTtCttactatCtTcAA578_2-19,318584578TTTTTTCTTACTATCTTCAA1-2-2-9-1-2-3Ttt TTtcttactatCttCAA578_3-20,058584578TTTTTTCTTACTATCTTCAA1-1-1-1-1-1-1-7-1-3-2TtTtTtCttactatCttcAA578_4-18,438584578TTTTTTCTTACTATCTTCAA3-3-1-8-1-2-2TTTtttCttactatcTtcAA578_5-18,998584578TTTTTTCTTACTATCTTCAA2-1-2-1-1-8-1-2-2TTtTTtCttactatcTtcAA578_6-19,298584578TTTTTTCTTACTATCTTCAA1-1-3-1-1-9-1-1-2TtTTTtCttactatctTcAA578_7-19,158584578TTTTTTCTTACTATCTTCAA2-1-1-11-1-1-3TTtTttcttactatcTtCAA578_8-19,588584578TTTTTTCTTACTATCTTCAA1-4-1-10-4TttttTcttactatctTCAA578_9-19,318584579TTTTTTTCTTACTATCTTCA1-12-1-1-1-2-2TttttttcttactAtCttCA579_1-19,298585579TTTTTTTCTTACTATCTTCA2-1-1-9-1-4-2TTtTtttcttactAtcttCA579_2-19,428585579TTTTTTTCTTACTATCTTCA1-1-1-2-1-7-1-4-2TtTttTtcttactAtcttCA579_3-18,918585579TTTTTTTCTTACTATCTTCA1-1-2-9-1-2-1-1-2TtTTtttcttactAtcTtCA579_4-19,948585579TTTTTTTCTTACTATCTTCA1-3-2-10-1-1-2TtttTTtcttactatcTtCA579_5-19,848585579TTTTTTTCTTACTATCTTCA2-3-1-12-2TTtttTtcttactatcttCA579_6-19,338585579TTTTTTTCTTACTATCTTCA3-15-2TTTttttcttactatcttCA579_7-19,848585579TTTTTTTCTTACTATCTTCA1-2-2-13-2Ttt TTttcttactatcttCA579_8-19,338585579TTTTTTTCTTACTATCTTCA1-14-1-2-2TttttttcttactatCttCA579_9-19,198585580ATTTTTTTCTTACTATCTTC1-4-1-8-1-1-1-1-2AttttTttcttactAtCtTC580_1-18,098586580ATTTTTTTCTTACTATCTTC2-1-1-10-1-2-3ATtTttttcttactAtcTTC580_2-19,398586580ACTTACTATCTTC1-3-2-8-1-2-3AtttTTttcttactAtcTTC580_3-18,958586580ATTTTTTTCTTACTATCTTC1-5-1-6-1-3-3AtttttTtcttacTatcTTC580_4-18,988586580ATTTTTTTCTTACTATCTTC2-2-1-1-1-7-1-3-2ATttTtTtcttactAtctTC580_5-18,668586580ATTTTTTTCTTACTATCTTC1-1-3-8-1-4-2AtTTTtttcttacTatctTC580_6-19,588586580ATTTTTTTCTTACTATCTTC2-1-1-12-1-1-2A TtTttttcttactatCtTC580_7-19,248586580ACTTACTATCTTC1-1-1-2-1-11-3AtTttTttcttactatcTTC580_8-18,348586580ATTTTTTTCTTACTATCTTC1-1-2-1-2-11-2AtTTtTTtcttactatctTC580_9-18,948586581AATTTTTTTCTTACTATCTT1-4-1-7-1-1-1-1-3AatttTtttcttaCtAtCTT581_1-18,538587581AATTTTTTTCTTACTATCTT1-3-1-1-1-6-2-3-2AattTtTttcttaCTatcTT581_2-18,698587581AATTTTTTTCTTACTATCTT1-1-2-10-2-2-2AaTTtttttcttacTAtcTT581_3-18,808587581AATTTTTTTCTTACTATCTT2-1-1-1-1-8-1-2-3AAtTtTtttcttacTatCTT581_4-19,208587581AATTTTTTTCTTACTATCTT4-2-1-7-1-3-2AATTttTttcttacTatcTT581_5-19,308587581AATTTTTTTCTTACTATCTT2-2-2-7-1-1-2-1-2AAttTTtttcttaCtATcTT581_6-19,528587581AATTTTTTTCTTACTATCTT1-12-1-2-4AatttttttcttaCta TCTT581_7-19,258587581AATTTTTTTCTTACTATCTT1-1-4-7-1-4-2AaTTTTtttcttaCtatcTT581_8-19,358587581AATTTTTTTCTTACTATCTT2-1-3-9-1-1-3AAtTTTtttcttactAtCTT581_9-19,688587582GTTTATACCCTTTCCAAT1-1-1-1-1-7-2-2-2GtTtAtacccttTCcaAT582_1-21,489209582GTTTATACCCTTTCCAAT1-12-2-1-2GtttataccctttCCaAT582_2-22,289209582GTTTATACCCTTTCCAAT1-3-1-8-1-1-3GtttAtaccctttCcAAT582_3-20,469209582GTTTATACCCTTTCCAAT1-1-1-1-1-9-1-1-2GtTtAtaccctttcCaAT582_4-20,309209582GTTTATACCCTTTCCAAT2-11-1-2-2GTttataccctttCcaAT582_5-21,649209582GTTTATACCCTTTCCAAT1-1-2-9-1-1-3GtTTataccctttCcAAT582_6-21,909209582GTTTATACCCTTTCCAAT1-1-1-13-2GtTtataccctttccaAT582_7-19,639209582GTTTATACCCTTTCCAAT1-2-1-12-2GttTataccctttccaAT582_8-20,059209582GTTTATACCCTTTCCAAT1-13-4GtttataccctttcCAAT582_9-21,599209583TGTTTATACCCTTTCCAA2-1-1-10-1-1-2TGtTtataccctttCcAA583_1-21,089210583TGTTTATACCCTTTCCAA1-4-1-6-1-1-1-1-2TgtttAtaccctTtCcAA583_2-19,979210583TGTTTATACCCTTTCCAA1-3-1-9-1-1-2TgttTataccctttCcAA583_3-20,309210583TGTTTATACCCTTTCCAA2-1-1-1-1-6-1-3-2TGtTtAtaccctTtccAA583_4-20,719210583TGTTTATACCCTTTCCAA1-2-1-8-1-2-3TgtTtataccctTtcCAA583_5-21,409210583TGTTTATACCCTTTCCAA1-4-1-9-3TgtttAtaccctttcCAA583_6-20,899210583TGTTTATACCCTTTCCAA1-1-2-12-2TgTTtataccctttccAA583_7-20,279210583TGTTTATACCCTTTCCAA1-12-2-1-2TgtttatacccttTCcAA583_8-20,569210583TGTTTATACCCTTTCCAA2-2-1-11-2TGttTataccctttccAA583_9-20,749210584CTGTTTATACCCTTTCCA1-1-1-10-1-2-2CtGtttataccctTtcCA584_1-22,459211584CTGTTTATACCCTTTCCA1-12-1-2-2CtgtttataccctTtcCA584_2-22,149211584CTGTTTATACCCTTTCCA1-1-1-1-1-11-2CtGtTtataccctttcCA584_3-22,459211584CTGTTTATACCCTTTCCA1-1-1-13-2CtGtttataccctttcCA584_4-22,159211584CTGTTTATACCCTTTCCA1-2-1-12-2CtgTttataccctttcCA584_5-22,509211584CTGTTTATACCCTTTCCA1-3-1-11-2CtgtTtataccctttcCA584_6-22,149211584CTGTTTATACCCTTTCCA1-4-1-10-2CtgttTataccctttcCA584_7-22,579211584CTGTTTATACCCTTTCCA1-15-2CtgtttataccctttcCA584_8-21,849211585AATTATTTATACACCATCAT2-1-1-1-1-8-3-1-2AAtTaTttatacacCATcAT585_1-20,7611511585AATTATTTATACACCATCAT3-2-2-6-1-1-2-1-2AATtaTTtatacaCcATcAT585_2-20,8811511585AATTATTTATACACCATCAT1-4-1-7-2-1-1-1-2AattaTttatacaCCaTcAT585_3-19,6211511585AATTATTTATACACCATCAT1-3-1-1-1-6-1-3-3AattAtTtatacaCcatCAT585_4-18,9811511585AATTATTTATACACCATCAT1-2-3-7-1-1-1-2-2AatTATttatacaCcAtcAT585_5-19,6511511585AATTATTTATACACCATCAT1-1-2-11-1-1-3AaTTatttatacaccAtCAT585_6-19,5311511585AATTATTTATACACCATCAT2-2-1-9-1-1-4AAttAtttatacacCaTCAT585_7-20,1111511585AATTATTTATACACCATCAT3-1-2-8-1-2-3AATtATttatacacCatCAT585_8-21,4811511585AATTATTTATACACCATCAT4-2-1-7-1-3-2AATTatTtatacacCatcAT585_9-19,6011511585AATTATTTATACACCATCAT2-1-1-2-1-6-3-2-2AAtTatTtatacaCCAtcAT585_10-21,6911511585AATTATTTATACACCATCAT1-3-2-7-1-1-1-1-3AattATttatacaCcAtCAT585_11-19,9711511585AATTATTTATACACCATCAT2-1-3-8-1-1-1-1-2AAtTATttatacacCaTcAT585_12-20,4211511585AATTATTTATACACCATCAT1-1-2-1-1-8-1-2-3AaTTaTttatacacCatCAT585_13-20,4911511585AATTATTTATACACCATCAT2-1-1-2-1-9-4AAtTatTtatacaccaTCAT585_14-20,4711511586AAATTATTTATACACCATCA1-12-3-1-3AaattatttatacACCaTCA586_1-20,5811512586AAATTATTTATACACCATCA1-1-1-2-1-7-1-1-2-1-2AaAttAtttatacAcCAtCA586_2-18,5611512586AAATTATTTATACACCATCA3-2-2-6-2-3-2AAAttATttatacACcatCA586_3-19,6811512586AAATTATTTATACACCATCA4-10-1-2-3AAA TtatttatacaCca TCA586_4-20,1511512586AAATTATTTATACACCATCA1-1-4-8-1-1-1-1-2AaATTAtttatacaCcAtCA586_5-20,7211512586AAATTATTTATACACCATCA2-1-2-1-1-7-1-3-2AAaTTaTttatacaCcatCA586_6-19,3911512586AAATTATTTATACACCATCA1-3-2-7-1-1-1-1-3AaatTAtttatacAcCaTCA586_7-19,6511512586AAATTATTTATACACCATCA1-1-3-8-1-2-4AaATTatttatacAccATCA586_8-20,8811512586AAATTATTTATACACCATCA2-2-1-1-1-9-4AAatTaTttatacaccATCA586_9-19,6311512586AAATTATTTATACACCATCA1-1-1-1-1-1-1-6-3-2-2AaAtTaTttatacACCatCA586_10-20,9511512586AAATTATTTATACACCATCA1-3-2-7-1-1-2-1-2AaatTAtttatacAcCAtCA586_11-20,0011512586AAATTATTTATACACCATCA2-1-2-1-1-7-1-1-1-1-2AAaTTaTttatacaCcAtCA586_12-19,4411512586AAATTATTTATACACCATCA3-2-1-8-1-2-3AAAttAtttatacaCca TCA586_13-19,0011512586AAATTATTTATACACCATCA1-1-4-9-1-1-3AaATTAtttatacacCaTCA586_14-21,5911512587AAAATTATTTATACACCATC2-3-1-7-1-1-5AAaatTatttataCaCCATC587_1-21,1711513587AAAATTATTTATACACCATC1-2-2-9-6AaaATtatttatacACCATC587_2-21,3411513587AAAATTATTTATACACCATC2-3-2-6-3-1-3AAaatTAtttataCACcATC587_3-20,6711513587AAAATTATTTATACACCATC3-1-1-1-1-7-3-1-2AAAaTtAtttatacACCaTC587_4-19,1111513587AAAATTATTTATACACCATC7-6-1-1-1-2-2AAAATTAtttataCaCcaTC587_5-20,6611513587AAAATTATTTATACACCATC1-1-1-1-2-8-2-1-3AaAaTTatttatacACcATC587_6-18,2011513587AAAATTATTTATACACCATC1-1-5-6-2-3-2AaAATTAtttataCAccaTC587_7-20,7111513587AAAATTATTTATACACCATC2-1-3-7-1-2-4AAaATTatttataCacCATC587_8-20,8711513587AAAATTATTTATACACCATC4-1-1-8-1-1-4AAAAtTatttatacAcCATC587_9-19,3011513587AAAATTATTTATACACCATC1-1-2-1-2-6-3-2-2AaAAtTAtttataCACcaTC587_10-20,1311513587AAAATTATTTATACACCATC1-2-3-7-1-1-2-1-2AaaATTatttataCaCCaTC587_11-20,4411513587AAAATTATTTATACACCATC3-1-2-7-1-2-4AAAaTTatttataCacCATC587_12-20,2711513587AAAATTATTTATACACCATC3-2-1-8-3-1-2AAAatTatttatacACCaTC587_13-19,3011513587AAAATTATTTATACACCATC2-1-3-8-2-1-3AAaATTatttatacACcATC587_14-19,5211513588TAAAATTATTTATACACCAT2-3-1-7-1-1-5TAaaaTtatttatAcACCAT588_1-20,1411514588TAAAATTATTTATACACCAT1-2-1-2-1-6-2-1-4TaaAatTatttatACaCCAT588_2-20,1511514588TAAAATTATTTATACACCAT1-1-1-1-2-8-1-1-4TaAaATtatttataCaCCAT588_3-20,4011514588TAAAATTATTTATACACCAT4-1-2-6-4-1-2TAAAaTTatttatACACcAT588_4-21,3611514588TAAAATTATTTATACACCAT1-3-3-6-3-1-3TaaaATTatttatACAcCAT588_5-21,0711514588TAAAATTATTTATACACCAT2-1-4-7-3-1-2TAaAATTatttataCACcAT588_6-21,3611514588TAAAATTATTTATACACCAT3-1-1-1-1-7-2-1-3TAAaAtTatttataCAcCAT588_7-20,4111514588TAAAATTATTTATACACCAT7-6-1-3-3TAAAATTatttatAcacCAT588_8-20,8511514588TAAAATTATTTATACACCAT2-1-2-11-4TAaAAttatttatacaCCAT588_9-19,8211514588TAAAATTATTTATACACCAT2-2-3-6-4-1-2TAaaATTatttatACACcAT588_10-21,4111514588TAAAATTATTTATACACCAT1-1-1-1-3-6-1-2-4TaAaATTatttatAcaCCAT588_11-21,1511514588TAAAATTATTTATACACCAT2-1-2-1-1-7-2-1-3TAaAAtTatttataCAcCAT588_12-20,4111514588TAAAATTATTTATACACCAT3-2-2-7-1-1-4TAAaaTTatttataCaCCAT588_13-21,8611514588TAAAATTATTTATACACCAT1-1-2-1-1-9-5TaAAaTtatttatacACCAT588_14-19,6811514589TAAAATTATTTATACACCA1-1-2-1-1-7-6TaAAaTtatttatACACCA589_1-20,3111515589TAAAATTATTTATACACCA1-2-3-6-1-1-5TaaAATtatttaTaCACCA589_2-21,3611515589TAAAATTATTTATACACCA2-3-1-7-6TAaaaTtatttatACACCA589_3-20,5811515589TAAAATTATTTATACACCA3-1-2-6-4-1-2TAAaATtatttaTACAcCA589_4-21,3611515589TAAAATTATTTATACACCA4-1-1-6-2-2-3TAAAaTtatttaTAcaCCA589_5-20,5111515589TAAAATTATTTATACACCA2-1-2-7-1-1-1-1-3TAaAAttatttaTaCaCCA589_6-19,3011515589TAAAATTATTTATACACCA1-3-2-6-2-2-3TaaaATtatttaTAcaCCA589_7-19,4011515589TAAAATTATTTATACACCA5-8-2-1-3TAAAAttatttatACaCCA589_8-19,7711515589TAAAATTATTTATACACCA3-1-2-9-4TAAaATtatttatacACCA589_9-19,5511515589TAAAATTATTTATACACCA2-1-3-6-4-1-2TAaAATtatttaTACAcCA589_10-21,3611515589TAAAATTATTTATACACCA3-1-2-6-3-1-3TAAaATtatttaTACaCCA589_11-22,1811515589TAAAATTATTTATACACCA1-1-3-7-2-1-4TaAAAttatttaTAcACCA589_12-19,7811515589TAAAATTATTTATACACCA2-2-1-7-1-1-1-1-3TAaaAttatttaTaCaCCA589_13-18,7611515589TAAAATTATTTATACACCA4-1-1-8-5TAAAaTtatttataCACCA589_14-21,0611515590ATATTGATTCAATTCCC2-9-2-1-3ATattgattcaATtCCC590_1-21,8413226590ATATTGATTCAATTCCC1-2-1-7-6AtaTtgattcaATTCCC590_2-22,1013226590ATATTGATTCAATTCCC2-9-1-1-1-1-2ATattgattcaAtTcCC590_3-18,5913226590ATATTGATTCAATTCCC1-1-2-8-5AtATtgattcaaTTCCC590_4-21,8713226590ATATTGATTCAATTCCC1-2-2-7-2-1-2AtaTTgattcaaTTcCC590_5-19,2913226590ATATTGATTCAATTCCC1-3-1-6-2-2-2AtatTgattcaATtcCC590_6-18,5913226590ATATTGATTCAATTCCC1-2-2-6-1-2-3AtaTTgattcaAttCCC590_7-20,6613226590ATATTGATTCAATTCCC1-1-1-1-1-7-1-1-3AtAtTgattcaaTtCCC590_8-19,9213226590ATATTGATTCAATTCCC1-1-1-8-1-2-3AtAttgattcaAttCCC590_9-19,0113226590ATATTGATTCAATTCCC4-7-1-3-2ATATtgattcaAttcCC590_10-20,6013226590ATATTGATTCAATTCCC3-1-1-7-1-2-2ATAtT gattcaaTtcCC590_11-20,2613226590ATATTGATTCAATTCCC1-3-1-8-4AtatTgattcaatTCCC590_12-20,3713226590ATATTGATTCAATTCCC2-1-1-10-3ATaTtgattcaattCCC590_13-20,7113226590ATATTGATTCAATTCCC2-2-1-9-3ATatTgattcaattCCC590_14-21,0613226590ATATTGATTCAATTCCC1-1-3-10-2AtATTgattcaattcCC590_15-18,8713226590ATATTGATTCAATTCCC2-2-1-6-2-2-2ATatTgattcaATtcCC590_16-20,2613226590ATATTGATTCAATTCCC3-8-1-1-4ATAttgattcaAtTCCC590_17-22,7113226590ATATTGATTCAATTCCC1-1-3-6-1-2-3AtATTgattcaAttCCC590_18-21,5713226590ATATTGATTCAATTCCC1-1-1-1-1-7-5AtAtTgattcaaTTCCC590_19-21,4213226590ATATTGATTCAATTCCC2-1-1-8-1-1-3ATaTtgattcaaTtCCC590_20-21,1513226591GCACATTCTTTCTATACCT1-1-1-1-1-12-2GcAcAttctttctatacCT591_1-21,2715113591GCACATTCTTTCTATACCT1-3-1-12-2GcacAttctttctatacCT591_2-21,1215113592GCACATTCTTTCTATACC1-12-1-2-2GcacattctttctAtaCC592_1-20,0715114592GCACATTCTTTCTATACC1-1-1-1-1-11-2GcAcAttctttctataCC592_2-20,1715114592GCACATTCTTTCTATACC1-3-1-11-2GcacAttctttctataCC592_3-20,0215114592GCACATTCTTTCTATACC1-1-2-11-3GcACattctttctatACC592_4-21,8015114592GCACATTCTTTCTATACC1-1-1-1-2-7-1-1-3GcAcATtctttctAtACC592_5-22,1115114592GCACATTCTTTCTATACC1-1-1-1-2-7-1-2-2GcAcATtctttctAtaCC592_6-21,5115114592GCACATTCTTTCTATACC1-15-2GcacattctttctataCC592_7-19,9715114592GCACATTCTTTCTATACC1-4-1-9-3GcacaTtctttctatACC592_8-21,0115114592GCACATTCTTTCTATACC1-4-1-10-2GcacaTtctttctataCC592_9-20,4115114592GCACATTCTTTCTATACC2-11-1- 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TCtcaactACcaTTT610_3-21,4625250610AAAATCTCAACTACCATTT2-2-2-7-2-1-3AAaaTCtcaactaCCaTTT610_4-21,1825250610AAAATCTCAACTACCATTT6-7-2-2-2AAAATCtcaactaCCatTT610_5-22,1025250610AAAATCTCAACTACCATTT2-1-1-1-1-8-5AAaAtCtcaactacCATTT610_6-20,2725250610AAAATCTCAACTACCATTT1-1-1-1-2-8-5AaAaTCtcaactacCATTT610_7-20,8825250610AAAATCTCAACTACCATTT1-1-2-1-1-8-2-1-2AaAAtCtcaactacCAtTT610_8-18,5125250610AAAATCTCAACTACCATTT6-9-4AAAATCtcaactaccATTT610_9-20,9425250611GAAAATCTCAACTACCATT1-1-3-7-1-2-4GaAAAtctcaacTacCATT611_1-20,4825251611GAAAATCTCAACTACCATT1-1-2-8-1-1-1-1-3GaAAatctcaacTaCcATT611_2-18,7525251611GAAAATCTCAACTACCATT3-1-1-10-4GAAaAtctcaactacCATT611_3-20,7325251611GAAAATCTCAACTACCATT2-1-2-10-4GAaAAtctcaactacCATT611_4-20,7325251611GAAAATCTCAACTACCATT2-2-1-7-1-4-2GAaaAtctcaacTaccaTT611_5-18,2825251611GAAAATCTCAACTACCATT2-12-5GAaaatctcaactaCCATT611_6-22,2525251611GAAAATCTCAACTACCATT4-10-2-1-2GAAAatctcaactaCCaTT611_7-21,0625251611GAAAATCTCAACTACCATT4-10-1-1-3GAAAatctcaactaCcATT611_8-19,7325251611GAAAATCTCAACTACCATT5-12-2GAAAAtctcaactaccaTT611_9-18,6125251612TGAAAATCTCAACTACCAT1-4-1-6-1-1-2-1-2TgaaaAtctcaaCtACcAT612_1-18,4325252612TGAAAATCTCAACTACCAT2-1-2-7-1-2-1-1-2TGaAAatctcaaCtaCcAT612_2-19,4625252612TGAAAATCTCAACTACCAT1-1-2-8-1-2-1-1-2TgAAaatctcaaCtaCcAT612_3-18,5825252612TGAAAATCTCAACTACCAT1-2-1-1-1-6-1-3-3TgaAaAtctcaaCtacCAT612_4-19,4025252612TGAAAATCTCAACTACCAT1-3-2-10-3TgaaAAtctcaactacCAT612_5-18,6025252612TGAAAATCTCAACTACCAT1-11-1-2-4TgaaaatctcaaCtaCCAT612_6-21,1125252612TGAAAATCTCAACTACCAT3-1-2-6-1-4-2TGAaAAtctcaaCtaccAT612_7-20,3925252612TGAAAATCTCAACTACCAT1-1-1-1-1-7-1-3-3TgAaAatctcaaCtacCAT612_8-19,6025252612TGAAAATCTCAACTACCAT4-12-3TGAAaatctcaactacCAT612_9-21,0725252613ATCATTCTCAACAATTAAA4-8-7ATCAttctcaacAATTAAA613_1-20,8930599613ATCATTCTCAACAATTAAA1-1-4-6-7AtCATTctcaacAATTAAA613_2-21,0930599613ATCATTCTCAACAATTAAA5-7-2-1-1-1-2ATCATtctcaacAAtTaAA613_3-19,0330599613ATCATTCTCAACAATTAAA5-8-2-2-2ATCATtctcaacaATtaAA613_4-19,2830599613ATCATTCTCAACAATTAAA4-1-1-8-5ATCAtTctcaacaaTTAAA613_5-19,8630599613ATCATTCTCAACAATTAAA5 7-4- 1-2ATCATtctcaacAATTaAA613_6-20,7930599613ATCATTCTCAACAATTAAA4-8-1-1-5ATCAttctcaacAaTTAAA613_7-19,5630599613ATCATTCTCAACAATTAAA1-1-4-6-1-1-5AtCATTctcaacAaTTAAA613_8-19,7630599613ATCATTCTCAACAATTAAA4-1-1-7-3-1-2ATCAtTctcaacaATTaAA613_9-19,6430599613ATCATTCTCAACAATTAAA5-8-1-1-4ATCATtctcaacaAtTAAA613_10-20,1130599614ATCATTCTCAACAATTAA4-8-6ATCAttctcaacAATTAA614_1-20,1430600614ATCATTCTCAACAATTAA1-1-4-6-6AtCATTctcaacAATTAA614_2-20,3430600614ATCATTCTCAACAATTAA5-8-1-1-3ATCATtctcaacaAtTAA614_3-19,3630600614ATCATTCTCAACAATTAA4-8-1-1-4ATCAttctcaacAaTTAA614_4-18,8130600614ATCATTCTCAACAATTAA5-8-5ATCATtctcaacaATTAA614_5-21,1230600614ATCATTCTCAACAATTAA5-7-1-2-3ATCATtctcaacAatTAA614_6-19,1130600614ATCATTCTCAACAATTAA3-10-5ATCattctcaacaATTAA614_7-18,4030600614ATCATTCTCAACAATTAA4-9-1-1-3ATCAttctcaacaAtTAA614_8-18,1130600614ATCATTCTCAACAATTAA4-1-1-8-4ATCAtTctcaacaaTTAA614_9-19,1130600614ATCATTCTCAACAATTAA1-1-3-9-4AtCATtctcaacaaTTAA614_10-18,0530600615GATCATTCTCAACAATTAA2-3-1-6-2-1-4GAtcaTtctcaaCAaTTAA615_1-20,5430600615GATCATTCTCAACAATTAA1-2-2-7-1-2-4GatCAttctcaaCaaTTAA615 2-19,0430600615GATCATTCTCAACAATTAA2-1-3-6-3-2-2GAtCATtctcaaCAAttAA615_3-21,2930600615GATCATTCTCAACAATTAA2-1-2-8-2-1-3GAtCAttctcaacAAtTAA615_4-19,7030600615GATCATTCTCAACAATTAA5-8-1-1-1-1-2GATCAttctcaacAaTtAA615_5-19,7930600615GATCATTCTCAACAATTAA4-8-3-2-2GATCattctcaaCAAttAA615_6-20,5030600615GATCATTCTCAACAATTAA1-2-3-6-2-2-3GatCATtctcaaCAatTAA615_7-20,8230600615GATCATTCTCAACAATTAA2-2-2-6-1-1-5GAtcATtctcaaCaATTAA615_8-21,0430600615GATCATTCTCAACAATTAA2-1-1-8-1-2-4GAtCattctcaaCaaTTAA615_9-19,2830600615GATCATTCTCAACAATTAA1-1-3-9-1-1-3GaTCAttctcaacaAtTAA615_10-18,8530600616AGATCATTCTCAACAATTA1-1-1-2-1-7-3-1-2AgAtcAttctcaaCAAtTA616_1-19,1030601616AGATCATTCTCAACAATTA1-3-1-8-2-1-3AgatCattctcaaCAaTTA616_2-19,6530601616AGATCATTCTCAACAATTA1-3-2-6-1-1-1-2-2AgatCAttctcaAcAatTA616_3-18,4930601616AGATCATTCTCAACAATTA1-1-1-1-2-11-2AgAtCAttctcaacaatTA616_4-18,4930601616AGATCATTCTCAACAATTA1-1-1-2-1-9-4AgAtcAttctcaacaATTA616_5-18,4930601616AGATCATTCTCAACAATTA1-3-2-6-1-1-5AgatC AttctcaAcAATTA616_6-20,7630601616AGATCATTCTCAACAATTA2-2-1-8-3-1-2AGatCattctcaaCAAtTA616_7-20,4730601616AGATCATTCTCAACAATTA3-2-1-7-1-2-3AGAtcAttctcaaCaaTTA616_8-20,5130601616AGATCATTCTCAACAATTA1-2-3-7-1-3-2AgaTCAttctcaaCaatTA616_9-19,8030601616AGATCATTCTCAACAATTA1-1-1-1-2-8-2-1-2AgAtCAttctcaacAAtTA616_10-19,0830601617GATCATTCTCAACAATTA2-3-1-6-6GAtca TtctcaaCAATT A617_1-21,1130601617GATCATTCTCAACAATTA2-1-2-8-5GAtCAttctcaacAATTA617_2-20,7130601617GATCATTCTCAACAATTA2-2-2-6-2-2-2GAtcATtctcaaCAatTA617_3-19,7030601617GATCATTCTCAACAATTA1-1-3-7-1-1-1-1-2GaTCAttctcaaCaAtTA617_4-18,7830601617GATCATTCTCAACAATTA2-1-2-10-3GAtCAttctcaacaaTTA617 5-19,3130601617GATCATTCTCAACAATTA2-1-1-1-1-6-3-1-2GAtCaTtctcaaCAAtTA617 6-20,0230601617GATCATTCTCAACAATTA2-1-2-7-2-2-2GAtCAttctcaaCAatTA617_7-20,5330601617GATCATTCTCAACAATTA2-1-3-6-1-2-3GAtCATtctcaaCaaTTA617_8-21,2430601617GATCATTCTCAACAATTA2-2-1-8-5GAtcAttctcaacAATTA617 9-18,6330601617GATCATTCTCAACAATTA1-1-3-9-1-1-2GaTCAttctcaacaAtTA617_10-18,1030601618AGATCATTCTCAACAATT1-3-2-6-6AgatCAttctcaACAATT618_1-21,0330602618AGATCATTCTCAACAATT1-1-1-1-2-7-5AgAtCAttctcaaCAATT618_2-20,7030602618AGATCATTCTCAACAATT1-1-4-6-1-3-2AgATCAttctcaAcaaTT618_3-19,5630602618AGATCATTCTCAACAATT3-1-1-9-4AGAtCattctcaacAATT618_4-19,6130602618AGATCATTCTCAACAATT2-1-3-10-2AGaTCAttctcaacaaTT618_5-19,0930602618AGATCATTCTCAACAATT1-2-3-6-1-3-2AgaTCAttctcaAcaaTT618_6-18,2530602618AGATCATTCTCAACAATT2-2-2-7-2-1-2AGatCAttctcaaCAaTT618_7-20,1430602618AGATCATTCTCAACAATT1-1-1-1-2-7-1-1-3AgAtCAttctcaaCaATT618_8-19,0230602618AGATCATTCTCAACAATT1-2-3-8-4AgaTCAttctcaacAATT618_9-19,2330602618AGATCATTCTCAACAATT3-1-1-10-3AGAtCattctcaacaATT618_10-19,3430602619GATCATTCTCAACAATT2-1-2-6-6GAtCAttctcaACAATT619_1-21,4030602619GATCATTCTCAACAATT1-1-3-7-5GaTCAttctcaaCAATT619_2-19,9930602619GATCATTCTCAACAATT5-7-1-2-2GATCAttctcaaCaaTT619_3-19,6930602619GATCATTCTCAACAATT5-6-1-1-4GATCAttctcaAcAATT619_4-20,8330602619GATCATTCTCAACAATT2-1-2-7-5GAtCAttctcaaCAATT619_5-20,5730602619GATCATTCTCAACAATT5-6-1-3-2GATCAttctcaAcaaTT619_6-19,4330602619GATCATTCTCAACAATT4-8-5GATCattctcaaCAATT619_7-21,0430602619GATCATTCTCAACAATT1-1-3-7-2-1-2GaTCAttctcaaCAaTT619_8-18,6730602619GATCATTCTCAACAATT5-7-1-1-3GATCAttctcaaCaATT619_9-20,8230602619GATCATTCTCAACAATT2-1-2-8-4GAtCAttctcaacAATT619_10-18,4830602620AAGATCATTCTCAACAAT4-1-1-6-1-1-4AAGAtCattctcAaCAAT620_1-20,7130603620AAGATCATTCTCAACAAT4-9-5AAGAtcattctcaACAAT620_2-20,7930603620AAGATCATTCTCAACAAT2-2-2-6-6AAgaTCattctcAACAAT620_3-19,8830603620AAGATCATTCTCAACAAT4-1-1-7-2-1-2AAGAtCattctcaACaAT620_4-19,7730603620AAGATCATTCTCAACAAT2-1-3-8-4AAgATCattctcaaCAAT620_5-20,1030603620AAGATCATTCTCAACAAT4-1-1-6-2-2-2AAGAtCattctcAAcaAT620_6-18,9630603620AAGATCATTCTCAACAAT3-1-2-6-1-1-4AAGaTCattctcAaCAAT620_7-20,1230603620AAGATCATTCTCAACAAT2-1-3-6-1-1-4AAgATCattctcAaCAAT620_8-20,1730603620AAGATCATTCTCAACAAT1-1-1-2-1-7-5AaGatCattctcaACAAT620_9-18,2130603620AAGATCATTCTCAACAAT4-1-1-8-4AAGAtCattctcaaCAAT620_10-20,6330603621AAAGATCATTCTCAACAA1-1-1-9-6AaAgatcattctCAACAA621_1-18,1330604621AAAGATCATTCTCAACAA1-1-3-7-2-1-3AaAGAtcattctCAaCAA621_2-20,0830604621AAAGATCATTCTCAACAA1-3-2-6-2-1-3AaagATcattctCAaCAA621_3-18,1130604621AAAGATCATTCTCAACAA1-2-2-7-1-1-4AaaGAtcattctCaACAA621_4-18,0730604621AAAGATCATTCTCAACAA5-10-3AAAGAtcattctcaaCAA621_5-18,6530604621AAAGATCATTCTCAACAA1-1-3-7-3-1-2AaAGAtcattctCAAcAA621_6-18,5930604621AAAGATCATTCTCAACAA4-8-2-1-3AAAGatcattctCAaCAA621_7-19,1030604621AAAGATCATTCTCAACAA3-1-1-7-2-1-3AAAgAtcattctCAaCAA621_8-18,3530604621AAAGATCATTCTCAACAA1-1-2-8-2-1-3AaAGatcattctCAaCAA621_9-18,3730604621AAAGATCATTCTCAACAA1-2-2-7-2-1-3AaaGAtcattctCAaCAA621_10-18,7430604621AAAGATCATTCTCAACAA5-7-1- 2-3AAAGAtcattctCaaCAA621_11-19,3230604622CAAAGATCATTCTCAACA1-1-2-8-6CaAAgatcattcTCAACA622_1-20,9330605622CAAAGATCATTCTCAACA2-1-1-9-5CAaAgatcattctCAACA622_2-20,6830605622CAAAGATCATTCTCAACA1-4-1-7-5CaaagAtcattctCAACA622_3-18,8630605622CAAAGATCATTCTCAACA4-1-1-7-1-2-2CAAAgAtcattctCaaCA622_4-19,4030605622CAAAGATCATTCTCAACA3-1-2-10-2CAAaGAtcattctcaaCA622_5-19,6730605622CAAAGATCATTCTCAACA4-8-2-2-2CAAAgatcattcTCaaCA622_6-20,1030605622CAAAGATCATTCTCAACA1-1-2-1-1-7-5CaAAgAtcattctCAACA622_7-20,2330605622CAAAGATCATTCTCAACA2-1-1-9-2-1-2CAaAgatcattctCAaCA622_8-19,6630605622CAAAGATCATTCTCAACA3-2-1-7-1-1-3CAAagAtcattctCaACA622_9-19,2130605622CAAAGATCATTCTCAACA1-3-2-7-1-2-2CaaaGAtcattctCaaCA622_10-18,3030605623CAAAGATCATTCTCAAC3-8-6CAAagatcattCTCAAC623_1-19,9530606623CAAAGATCATTCTCAAC2-1-1-7-6CAaAgatcattCTCAAC623_2-20,2330606623CAAAGATCATTCTCAAC2-2-1-6-6CAaaGatcattCTCAAC623_3-20,1530606623CAAAGATCATTCTCAAC1-2-2-6-6CaaAGatcattCTCAAC623_4-20,0030606623CAAAGATCATTCTCAAC5-6-1-1-4CAAAGatcattCtCAAC623_5-20,3530606623CAAAGATCATTCTCAAC4-7-3-1-2CAAAgatcattCTCaAC623_6-19,2830606623CAAAGATCATTCTCAAC3-1-1-6-1-1-4CAAaGatcattCtCAAC623_7-18,8130606623CAAAGATCATTCTCAAC2-1-1-7-1-1-4CAaAgatcattCtCAAC623_8-18,3630606623CAAAGATCATTCTCAAC1-2-2-6-1-1-4CaaAGatcattCtCAAC623_9-18,1230606623CAAAGATCATTCTCAAC4-8-5CAAAgatcattcTCAAC623_10-19,3130606624CTCAAAGATCATTCTCA1-2-1-7-6CtcAaagatcaTTCTCA624_1-20,5730608624CTCAAAGATCATTCTCA1-1-1-1-1-7-2-1-2CtCaAagatcatTCtCA624_2-18,6930608624CTCAAAGATCATTCTCA1-1-2-7-1-2-3CtCAaagatcaTtcTCA624_3-19,5130608624CTCAAAGATCATTCTCA3-10-1-1-2CTCaaagatcattCtCA624_4-19,2330608624CTCAAAGATCATTCTCA1-1-3-8-4CtCAAagatcattCTCA624_5-21,2630608624CTCAAAGATCATTCTCA1-1-3-6-1-1-1-1-2CtCAAagatca TtCtCA624_6-19,8230608624CTCAAAGATCATTCTCA4-7-1-3-2CTCAaagatcaTtctCA624_7-20,1830608624CTCAAAGATCATTCTCA1-2-2-7-5CtcAAagatcatTCTCA624_8-20,1630608624CTCAAAGATCATTCTCA1-1-2-8-2-1-2CtCAaagatcatTCtCA624_9-19,8330608624CTCAAAGATCATTCTCA3-10-4CTCaaagatcattCTCA624_10-21,1130608625TACACTTAATTATACTTCCA1-2-1-1-1-7-2-3-2TacAcTtaattatACttcCA625_1-20,3330666625TACACTTAATTATACTTCCA1-2-1-2-1-6-1-4-2TacActTaattatActtcCA625_2-19,1530666625TACACTTAATTATACTTCCA1-4-1-7-1-1-1-2-2TacacTtaattatAcTtcCA625_3-19,3030666625TACACTTAATTATACTTCCA1-1-1-2-2-6-1-4-2TaCacTTaattatActtcCA625_4-20,7130666625TACACTTAATTATACTTCCA1-1-1-3-1-8-1-2-2TaCactTaattatacTtcCA625_5-20,0030666625TACACTTAATTATACTTCCA1-2-1-1-2-8-1-2-2TacAcTTaattatacTtcCA625_6-20,5030666625TACACTTAATTATACTTCCA1-2-1-13-3TacActtaattatacttCCA625_7-20,6030666625TACACTTAATTATACTTCCA1-4-1-11-3TacacTtaattatacttCCA625_8-20,9630666625TACACTTAATTATACTTCCA2-1-1-1-1-12-2TAcAcTtaattatacttcCA625_9-19,9730666625TACACTTAATTATACTTCCA1-1-1-2-1-7-2-3-2TaCacTtaattatACttcCA625_10-20,8730666625TACACTTAATTATACTTCCA1-2-1-1-2-6-1-1-1-2-2TacAcTTaattatAcTtcCA625_11-20,6930666625TACACTTAATTATACTTCCA1-2-1-1-1-9-1-1-3TacAcTtaattatacTtCCA625_12-21,6330666625TACACTTAATTATACTTCCA1-1-1-3-1-10-3TaCactTaattatacttCCA625_13-21,8630666625TACACTTAATTATACTTCCA2-1-2-1-1-11-2TAcACtTaattatacttcCA625_14-21,5830666626TTACACTTAATTATACTTCC1-3-1-1-1-7-2-2-2TtacAcTtaattatACttCC626_1-19,9830667626TTACACTTAATTATACTTCC1-5-1-7-1-1-1-1-2TtacacTtaattatAcTtCC626_2-18,9630667626TTACACTTAATTATACTTCC2-4-1-11-2TTacacTtaattatacttCC626_3-19,4930667626TTACACTTAATTATACTTCC1-5-1-9-4TtacacTtaattatacTTCC626_4-20,2630667626TTACACTTAATTATACTTCC1-1-1-3-1-8-1-2-2TtAcacTtaattataCttCC626_5-19,4330667626TTACACTTAATTATACTTCC1-1-2-2-1-7-1-3-2TtACacTtaattatActtCC626_6-19,7230667626TTACACTTAATTATACTTCC3-1-1-12-3TTAcActtaattatactTCC626_7-21,3330667626TTACACTTAATTATACTTCC1-1-1-1-1-1-1-9-1-1-2TtAcAcTtaattatacTtCC626_8-19,1030667626TTACACTTAATTATACTTCC1-2-2-1-1-11-2TtaCAcTtaattatacttCC626_9-20,4930667626TTACACTTAATTATACTTCC1-5-1-7-2-1-3TtacacTtaattatACtTCC626_10-20,8230667626TTACACTTAATTATACTTCC4-2-1-7-1-3-2TTACacTtaattatActtCC626_11-21,9930667626TTACACTTAATTATACTTCC1-1-1-1-3-8-1-2-2TtAcACTtaattataCttCC626_12-21,6530667626TTACACTTAATTATACTTCC2-1-2-11-4TTaCActtaattatacTTCC626_13-23,2330667626TTACACTTAATTATACTTCC2-2-1-1-1-9-1-1-2TTacAcTtaattatacTtCC626_14-20,1530667627TTTACACTTAATTATACTTC2-1-2-8-1-1-5TTtACacttaattAtACTTC627_1-20,0230668627TTTACACTTAATTATACTTC2-3-1-7-4-1-2TTtacActtaattATACtTC627_2-19,8930668627TTTACACTTAATTATACTTC1-2-1-1-1-7-2-1-4TttAcActtaattA T aCTTC627_3-19,3530668627TTTACACTTAATTATACTTC1-1-3-8-3-2-2TtTACacttaattATActTC627_4-20,5830668627TTTACACTTAATTATACTTC3-2-1-7-3-1-3TTTacActtaattATAcTTC627_5-20,7630668627TTTACACTTAATTATACTTC1-3-2-7-2-2-3TttaCActtaattATacTTC627_6-19,5830668627TTTACACTTAATTATACTTC3-2-1-7-2-1-4TTTacActtaattATaCTTC627_7-21,2130668627TTTACACTTAATTATACTTC3-1-1-8-1-2-4TTTaCacttaattAtaCTTC627_8-20,0730668627TTTACACTTAATTATACTTC6-7-1-4-2TTTACActtaattAtactTC627_9-20,5630668627TTTACACTTAATTATACTTC4-1-1-7-4-1-2TTTAcActtaattATACtTC627_10-22,3630668627TTTACACTTAATTATACTTC3-1-1-1-1-6-3-1-3TTTaCaCttaattATAcTTC627_11-22,2930668627TTTACACTTAATTATACTTC2-1-3-7-3-2-2TTtACActtaattATActTC627_12-21,1930668627TTTACACTTAATTATACTTC3-1-2-7-2-1-4TTTaCActtaattATaCTTC627 13-23,3030668627TTTACACTTAATTATACTTC1-1-4-7-1-2-4TtTACActtaattAtaCTTC627_14-21,9430668628ATTTACACTTAATTATACTT2-1-1-2-1-6-3-1-3ATtTacActtaatTATaCTT628_1-21,2130669628ATTTACACTTAATTATACTT3-1-1-8-2-1-4ATTtAcacttaatTAtACTT628_2-20,2730669628ATTTACACTTAATTATACTT1-1-2-2-1-6-4-1-2AtTTacActtaatTATAcTT628_3-20,3330669628ATTTACACTTAATTATACTT1-3-1-1-1-7-6AtttAcActtaattATACTT628_4-19,3030669628ATTTACACTTAATTATACTT2-2-2-7-3-2-2ATttACacttaatTATacTT628_5-19,9430669628ATTTACACTTAATTATACTT4-1-2-6-2-3-2ATTTaCActtaatTAtacTT628_6-21,2930669628ATTTACACTTAATTATACTT1-1-4-7-1-1-1-2-2AtTTACacttaatTaTacTT628_7-19,3330669628ATTTACACTTAATTATACTT2-2-3-6-1-2-4ATttACActtaatTatACTT628_8-20,9730669628ATTTACACTTAATTATACTT4-2-1-6-1-3-3ATTTacActtaatTataCTT628_9-19,7330669628ATTTACACTTAATTATACTT1-1-2-1-2-6-4-1-2AtTTaCAcrtaatTATAcTT628_10-22,4330669628ATTTACACTTAATTATACTT3-2-2-6-2-2-3ATTtaCActtaatTAtaCTT628_11-21,7230669628ATTTACACTTAATTATACTT1-2-4-6-2-2-3AttTACActtaatTAtaCTT628_12-22,0230669628ATTTACACTTAATTATACTT2-1-1-1-2-6-1-1-5ATtTaCActtaatTaTACTT628_13-23,0030669628ATTTACACTTAATTATACTT5-8-1-1-1-1-3ATTTAcacttaatTaTaCTT628_14-21,6830669629TTCTACTATACTTTCCTCT1-3-1-7-1-1-1-2-2TtctActatactTtCctCT629_1-21,0430711629TTCTACTATACTTTCCTCT1-11-1-1-1-2-2TtctactatactTtCctCT629_2-20,8530711629TTCTACTATACTTTCCTCT1-11-1-2-1-1-2TtctactatactTtcCtCT629_3-20,9730711629TTCTACTATACTTTCCTCT1-1-1-9-1-4-2TtCtactatactTtcctCT629_4-21,0630711629TTCTACTATACTTTCCTCT1-1-1-11-1-2-2TtCtactatactttCctCT629_5-21,5330711629TTCTACTATACTTTCCTCT1-3-1-9-1-2-2TtctActatactttCctCT629_6-20,7430711629TTCTACTATACTTTCCTCT1-4-1-8-1-2-2TtctaCtatactttCctCT629_7-21,5430711629TTCTACTATACTTTCCTCT1-13-1-2-2TtctactatactttCctCT629_8-20,5530711629TTCTACTATACTTTCCTCT1-1-1-12-1-1-2TtCtactatactttcCtCT629_9-21,6530711629TTCTACTATACTTTCCTCT1-3-1-10-1-1-2TtctActatactttcCtCT629_10-20,8630711629TTCTACTATACTTTCCTCT1-14-1-1-2TtctactatactttcCtCT629_11-20,6730711629TTCTACTATACTTTCCTCT1-1-1-1-1-7-1-1-1-2-2TtCtActatactTtCctCT629_12-22,0230711629TTCTACTATACTTTCCTCT1-1-1-2-1-8-1-2-2TtCtaCtatactttCctCT629_13-22,5230711629TTCTACTATACTTTCCTCT1-3-2-8-1-2-2TtctACtatactttCctCT629_14-22,1430711629TTCTACTATACTTTCCTCT1-1-1-1-1-10-1-1-2TtCtActatactttcCtCT629_15-21,8430711629TTCTACTATACTTTCCTCT1-1-1-2-1-9-1-1-2TtCtaCtatactttcCtCT629_16-22,6430711630GTTCTACTATACTTTCCTC1-12-1-1-1-1-2GttctactatactTtCcTC630_1-20,7830712630GTTCTACTATACTTTCCTC1-4-1-9-1-1-2GttctActatactttCcTC630_2-20,6730712630GTTCTACTATACTTTCCTC1-14-1-1-2GttctactatactttCcTC630_3-20,4830712631GTTCTACTATACTTTCCT1-2-1-1-1-7-1-2-2GttCtActatactTtcCT631_1-20,2530713631GTTCTACTATACTTTCCT1-2-1-9-1-2-2GttCtactatactTtcCT631_2-20,0630713631GTTCTACTATACTTTCCT1-2-1-11-3GttCtactatactttCCT631_3-22,1330713631GTTCTACTATACTTTCCT1-4-1-9-3GttctActatactttCCT631_4-21,3430713631GTTCTACTATACTTTCCT1-14-3GttctactatactttCCT631_5-21,1530713631GTTCTACTATACTTTCCT2-1-1-1-1-10-2GTtCtActatactttcCT631_6-21,5030713631GTTCTACTATACTTTCCT2-1-1-12-2GTtCtactatactttcCT631_7-21,3030713631GTTCTACTATACTTTCCT1-2-1-1-1-10-2GttCtActatactttcCT631_8-19,9530713631GTTCTACTATACTTTCCT1-2-1-12-2GttCtactatactttcCT631_9-19,7630713631GTTCTACTATACTTTCCT1-15-2GttctactatactttcCT631_10-18,7830713631GTTCTACTATACTTTCCT1-2-1-9-1-1-3GttCtactatactTtCCT631_11-22,4330713631GTTCTACTATACTTTCCT2-1-1-1-1-7-1-2-2GTtCtActatactTtcCT631_12-21,8030713631GTTCTACTATACTTTCCT1-2-2-8-1-2-2GttCTactatactTtcCT631_13-21,6830713631GTTCTACTATACTTTCCT1-2-1-1-1-9-3GttCtActatactttCCT631_14-22,3230713631GTTCTACTATACTTTCCT1-2-3-10-2GttCTActatactttcCT631_15-22,6030713632AGTTCTACTATACTTTCC1-12-1-2-2AgttctactatacTttCC632_1-19,3730714632AGTTCTACTATACTTTCC1-13-1-1-2AgttctactatactTtCC632_2-19,1630714632AGTTCTACTATACTTTCC1-1-1-13-2AgTtctactatactttCC632_3-19,5130714632AGTTCTACTATACTTTCC1-15-2AgttctactatactttCC632_4-18,8630714632AGTTCTACTATACTTTCC1-1-1-10-1-2-2AgTtctactatacTttCC632_5-20,0330714632AGTTCTACTATACTTTCC1-4-1-7-1-2-2AgttcTactatacTttCC632_6-20,3130714632AGTTCTACTATACTTTCC2-14-2AGttctactatactttCC632_7-20,2630714632AGTTCTACTATACTTTCC1-2-1-12-2AgtTctactatactttCC632_8-19,2330714632AGTTCTACTATACTTTCC1-4-1-10-2AgttcTactatactttCC632_9-19,8030714632AGTTCTACTATACTTTCC2-10-1-3-2AGttctactataCtttCC632_10-21,2530714632AGTTCTACTATACTTTCC1-4-1-6-1-3-2AgttcTactataCtttCC632_11-20,7930714632AGTTCTACTATACTTTCC1-4-1-7-2-1-2AgttcTactatacTTtCC632_12-21,1330714632AGTTCTACTATACTTTCC1-1-1-11-1-1-2AgTtctactatactTtCC632_13-19,8230714632AGTTCTACTATACTTTCC1-3-1-11-2AgttCtactatactttCC632_14-19,8330714633CAACATTATTAACCACCTTA1-13-3-1-2CaacattattaaccACCtTA633_1-22,4433376633CAACATTATTAACCACCTTA4-10-1-2-3CAACattattaaccAccTTA633_2-22,9833376633CAACATTATTAACCACCTTA2-2-1-10-1-1-3CAacAttattaaccaCcTTA633_3-21,9733376633CAACATTATTAACCACCTTA1-4-2-8-1-2-2CaacaTTattaaccaCctTA633_4-21,0833376633CAACATTATTAACCACCTTA1-1-2-11-1-2-2CaACattattaaccaCctTA633_5-20,9033376633CAACATTATTAACCACCTTA1-2-2-13-2CaaCAttattaaccacctTA633_6-20,7633376633CAACATTATTAACCACCTTA1-1-1-1-1-11-1-1-2CaAcAttattaaccacCtTA633_7-19,9733376633CAACATTATTAACCACCTTA1-15-4CaacattattaaccacCTTA633_8-21,2133376633CAACATTATTAACCACCTTA2-4-1-11-2CAacatTattaaccacctTA633_9-20,8333376634CAACATTATTAACCACCTT2-10-2-3-2CAacattattaaCCaccTT634_1-21,8633377634CAACATTATTAACCACCTT1-14-4CaacattattaaccaCCTT634_2-21,3633377634CAACATTATTAACCACCTT1-1-1-11-1-1-3CaAcattattaaccAcCTT634_3-19,5433377634CAACATTATTAACCACCTT3-1-1-11-3CAAcAttattaaccacCTT634_4-21,1333377634CAACATTATTAACCACCTT3-11-2-1-2CAAcattattaaccACcTT634_5-20,8433377634CAACATTATTAACCACCTT2-1-2-9-1-1-3CAaCAttattaaccAcCTT634_6-22,7633377634CAACATTATTAACCACCTT2-1-2-10-1-1-2CAaCAttattaaccaCcTT634_7-21,8333377634CAACATTATTAACCACCTT1-1-2-11-1-1-2CaACattattaaccaCcTT634_8-19,7033377634CAACATTATTAACCACCTT1-2-1-12-3CaaCattattaaccacCTT634_9-19,6633377635GCAACATTATTAACCACCT1-1-1-2-1-6-2-3-2GcAacAttattaACcacCT635_1-21,5633378635GCAACATTATTAACCACCT1-1-2-1-1-6-1-2-1-1-2GcAAcAttattaAccAcCT635_2-21,1433378635GCAACATTATTAACCACCT1-11-2-1-1-1-2GcaacattattaACcAcCT635_3-21,5933378635GCAACATTATTAACCACCT1-4-1-6-1-3-3GcaacAttattaAccaCCT635_4-22,6933378635GCAACATTATTAACCACCT1-1-1-1-1-7-1-4-2GcAaCattattaAccacCT635_5-21,0133378635GCAACATTATTAACCACCT1-11-1-1-1-2-2GcaacattattaAcCacCT635_6-20,8333378635GCAACATTATTAACCACCT2-3-1-6-1-4-2GCaacAttattaAccacCT635_7-22,6333378635GCAACATTATTAACCACCT1-1-1-12-1-1-2GcAacattattaaccAcCT635_8-20,0533378635GCAACATTATTAACCACCT1-2-1-1-1-11-2GcaAcAttattaaccacCT635_9-20,3033378636AGCAACATTATTAACCACC1-2-1-9-2-1-3AgcAacattattaACcACC636_1-22,1333379636AGCAACATTATTAACCACC1-11-1-1-1-2-2AgcaacattattAaCcaCC636_2-20,8033379636AGCAACATTATTAACCACC1-4-1-6-2-3-2AgcaaCattattAAccaCC636_3-21,3233379636AGCAACATTATTAACCACC1-2-2-7-1-2-1-1-2AgcAAcattattAacCaCC636_4-21,2933379636AGCAACATTATTAACCACC2-11-1-3-2AGcaacattattaAccaCC636_5-21,7533379636AGCAACATTATTAACCACC1-1-1-1-1-8-1-2-3AgCaAcattattaAccACC636_6-22,1633379636AGCAACATTATTAACCACC1-2-1-1-1-6-1-3-3AgcAaCattattAaccACC636_7-21,3333379636AGCAACATTATTAACCACC2-1-2-12-2AGcAAcattattaaccaCC636_8-22,0233379636AGCAACATTATTAACCACC1-15-3AgcaacattattaaccACC636_9-20,4533379637AGCAACATTATTAACCAC2-1-1-9-5AGcAacattattaACCAC637_1-21,9733380637AGCAACATTATTAACCAC1-3-1-7-6AgcaAcattattAACCAC637_2-21,2033380637AGCAACATTATTAACCAC2-10-2-1-3AGcaacattattAAcCAC637_3-19,4233380637AGCAACATTATTAACCAC1-2-1-8-1-1-4AgcAacattattAaCCAC637_4-19,8433380637AGCAACATTATTAACCAC3-9-3-1-2AGCaacattattAACcAC637_5-20,9433380637AGCAACATTATTAACCAC1-1-3-7-3-1-2AgCAAcattattAACcAC637_6-20,1533380637AGCAACATTATTAACCAC1-1-3-7-2-1-3AgCAAcattattAAcCAC637_7-20,9633380637AGCAACATTATTAACCAC5-7-1-3-2AGCAAcattattAaccAC637_8-21,2433380_637AGCAACATTATTAACCAC3-1-1-8-1-2-2AGCaAcattattaAccAC637_9-19,8633380638GTTTCCATCTACTATTAAT1-3-1-7-1-1-1-1-3GtttCcatctacTaTtAAT638_1-19,5939806638GTTTCCATCTACTATTAAT1-1-1-9-2-3-2GtTtccatctacTAttaAT638_2-19,5039806638GTTTCCATCTACTATTAAT1-4-1-6-2-2-3GtttcCatctacTAttAAT638_3-20,0939806638GTTTCCATCTACTATTAAT1-3-1-8-1-2-3GtttCcatctactAttAAT638_4-18,3039806638GTTTCCATCTACTATTAAT3-1-1-8-1-3-2GTTtCcatctactAttaAT638_5-20,3539806638GTTTCCATCTACTATTAAT1-2-2-12-2GttTCcatctactattaAT638_6-18,8839806638GTTTCCATCTACTATTAAT1-1-1-11-1-1-3GtTtccatctactaTtAAT638_7-18,1839806638GTTTCCATCTACTATTAAT2-2-1-10-1-1-2GTttCcatctactatTaAT638_8-20,1639806638GTTTCCATCTACTATTAAT1-1-1-1-2-10-3GtTtCCatctactattAAT638_9-20,6939806638GTTTCCATCTACTATTAAT2-2-1-7-1-3-3GTttCcatctacTattAAT638_10-20,6939806638GTTTCCATCTACTATTAAT1-1-1-10-2-1-3GtTtccatctactATtAAT638_11-19,0839806638GTTTCCATCTACTATTAAT1-3-1-8-1-1-1-1-2GtttCcatctactAtTaAT638_12-18,7239806638GTTTCCATCTACTATTAAT1-2-3-7-1-2-3GttTCCatctactAttAAT638_13-21,4739806638GTTTCCATCTACTATTAAT1-1-1-1-2-11-2GtTtCCatctactattaAT638_14-20,3739806639GTTTCCATCTACTATTAA1-11-2-1-3GtttccatctacTAtTAA639_1-19,2139807639GTTTCCATCTACTATTAA1-3-1-7-1-1-4GtttCcatctacTaTTAA639_2-19,8039807639GTTTCCATCTACTATTAA3-1-1-7-2-2-2GTTtCcatctacTAttAA639_3-20,5739807639GTTTCCATCTACTATTAA2-2-1-7-1-1-1-1-2GTttCcatctacTaTtAA639_4-19,0739807639GTTTCCATCTACTATTAA1-3-2-7-2-1-2GtttCCatctactATtAA639_5-19,6739807639GTTTCCATCTACTATTAA3-2-1-6-1-3-2GTTtcCatctacTattAA639_6-19,2539807639GTTTCCATCTACTATTAA1-1-3-8-1-2-2GtTTCcatctactAttAA639_7-18,0439807639GTTTCCATCTACTATTAA1-1-1-1-2-10-2GtTtCCatctactattAA639_8-18,6239807639GTTTCCATCTACTATTAA3-1-1-9-4GTTtCcatctactaTTAA639_9-21,2139807639GTTTCCATCTACTATTAA1-3-2-6-2-2-2GtttCCatctacTAttAA639_10-20,3939807639GTTTCCATCTACTATTAA1-1-3-7-1-1-1-1-2GtTTCcatctacTaTtAA639_11-19,3239807639GTTTCCATCTACTATTAA2-2-1-7-1-2-3GTttCcatctacTatTAA639_12-20,3939807639GTTTCCATCTACTATTAA2-2-1-8-2-1-2GTttCcatctactATtAA639_13-19,0339807639GTTTCCATCTACTATTAA1-1-1-1-2-8-4GtTtCCatctactaTTAA639_14-21,3439807640TGTTTCCATCTACTATTA1-1-1-11-1-1-2TgTttccatctactAtTA640_1-18,4139808640TGTTTCCATCTACTATTA1-2-1-9-2-1-2TgtTtccatctacTAtTA640_2-20,0339808_640TGTTTCCATCTACTATTA1-4-1-7-1-2-2TgtttCcatctacTatTA640_3-19,3739808640TGTTTCCATCTACTATTA1-4-1-8-4TgtttCcatctactATTA640_4-20,2839808640TGTTTCCATCTACTATTA1-4-1-8-1-1-2TgtttCcatctactAtTA640_5-18,5239808640TGTTTCCATCTACTATTA1-1-2-1-1-10-2TgTTtCcatctactatTA640_6-19,8939808640TGTTTCCATCTACTATTA1-4-1-9-3TgtttCcatctactaTTA640_7-19,3739808640TGTTTCCATCTACTATTA1-2-1-1-1-10-2TgtTtCcatctactatTA640_8-18,7339808640TGTTTCCATCTACTATTA1-4-1-10-2TgtttCcatctactatTA640_9-18,4239808640TGTTTCCATCTACTATTA1-4-1-6-1-1-4TgtttCcatctaCtATTA640_10-21,2739808640TGTTTCCATCTACTATTA2-1-1-9-2-1-2TGtTtccatctacTAtTA640_11-21,2439808640TGTTTCCATCTACTATTA1-3-2-8-1-1-2TgttTCcatctactAtTA640_12-19,5139808640TGTTTCCATCTACTATTA2-1-1-1-1-10-2TGtTtCcatctactatTA640_13-19,9439808640TGTTTCCATCTACTATTA1-1-1-2-1-10-2TgTttCcatctactatTA640_14-19,0839808641ACTCTGCAATACACCAA2-1-1-8-2-1-2ACtCtgcaatacACcAA641_1-19,6144439641ACTCTGCAATACACCAA2-2-1-6-1-1-1-1-2ACtcTgcaataCaCcAA641_2-19,7744439641ACTCTGCAATACACCAA1-2-1-7-1-1-1-1-2ActCtgcaataCaCcAA641_3-18,3544439641ACTCTGCAATACACCAA2-1-2-6-2-2-2ACtCTgcaataCAccAA641_4-22,2144439641ACTCTGCAATACACCAA1-3-1-7-1-1-3ActcTgcaatacAcCAA641_5-19,0544439641ACTCTGCAATACACCAA4-8-1-2-2ACTCtgcaatacAccAA641_6-20,3044439641ACTCTGCAATACACCAA2-1-2-9-3ACtCTgcaatacacCAA641_7-21,9644439641ACTCTGCAATACACCAA2-11-4ACtctgcaatacaCCAA641_8-21,6844439641ACTCTGCAATACACCAA1-1-2-10-3AcTCtgcaatacacCAA641_9-20,0744439642CTGTATACACCATCCCA1-10-1-1-1-1-2CtgtatacaccAtCcCA642_1-21,9946391642CTGTATACACCATCCCA1-10-1-3-2CtgtatacaccAtccCA642_2-21,2246391642CTGTATACACCATCCCA1-1-1-8-1-3-2CtGtatacaccAtccCA642_3-21,5346391642CTGTATACACCATCCCA1-2-1-7-1-3-2CtgTatacaccAtccCA642_4-22,3146391642CTGTATACACCATCCCA1-3-1-6-1-3-2CtgtAtacaccAtccCA642_5-21,3246391642CTGTATACACCATCCCA1-11-2-1-2CtgtatacaccaTCcCA642_6-23,0646391642CTGTATACACCATCCCA1-1-1-1-1-8-1-1-2CtGtAtacaccatCcCA642_7-22,3546391642CTGTATACACCATCCCA1-1-1-10-1-1-2CtGtatacaccatCcCA642_8-22,2546391642CTGTATACACCATCCCA1-2-1-9-1-1-2CtgTatacaccatCcCA642_9-23,0246391642CTGTATACACCATCCCA1-3-1-8-1-1-2CtgtAtacaccatCcCA642_10-22,0446391642CTGTATACACCATCCCA1-12-1-1-2CtgtatacaccatCcCA642_11-21,9446391642CTGTATACACCATCCCA2-2-1-10-2CTgtAtacaccatccCA642_12-22,9546391642CTGTATACACCATCCCA1-1-1-1-1-10-2CtGtAtacaccatccCA642_13-21,5846391642CTGTATACACCATCCCA1-1-1-12-2CtGtatacaccatccCA642_14-21,4846391642CTGTATACACCATCCCA1-2-2-10-2CtgTAtacaccatccCA642_15-23,3946391642CTGTATACACCATCCCA1-3-1-10-2CtgtAtacaccatccCA642_16-21,2746391642CTGTATACACCATCCCA1-14-2CtgtatacaccatccCA642_17-21,1746391642CTGTATACACCATCCCA1-3-1-6-31-2CtgtAtacaccATCcCA642_18-24,0246391642CTGTATACACCATCCCA1-1-1-8-1-1-1-1-2CtGtatacaccAtCcCA642_19-22,3046391642CTGTATACACCATCCCA1-1-3-6-1-3-2CtGTAtacaccAtccCA642_20-24,6446391642CTGTATACACCATCCCA2-2-1-8-1-1-2CTgtAtacaccatCcCA642_21-23,7246391642CTGTATACACCATCCCA1-3-1-9-3CtgtAtacaccatcCCA642_22-23,5546391643TCTGTATACACCATCCCA1-4-1-8-1-1-2TctgtAtacaccatCcCA643_1-22,9446391644TCTGTATACACCATCCC2-10-1-2-2TCtgtatacaccAtcCC644_1-22,7046392644TCTGTATACACCATCCC1-11-1-2-2TctgtatacaccAtcCC644_2-21,1146392644TCTGTATACACCATCCC2-1-1-11-2TCtGtatacaccatcCC644_3-22,9646392644TCTGTATACACCATCCC2-13-2TCtgtatacaccatcCC644_4-22,6546392644TCTGTATACACCATCCC3-9-1-2-2TCTgtatacaccAtcCC644_5-24,3946392644TCTGTATACACCATCCC2-1-1-8-1-2-2TCtGtatacaccAtcCC644_6-23,0146392645TTCTGTATACACCATCCC1-11-1-3-2TtctgtatacacCatcCC645_1-22,5746392645TTCTGTATACACCATCCC1-1-1-10-1-2-2TtCtgtatacaccAtcCC645_2-23,0246392645TTCTGTATACACCATCCC1-3-1-8-1-2-2TtctGtatacaccAtcCC645_3-22,3646392645TTCTGTATACACCATCCC1-12-1-2-2TtctgtatacaccAtcCC645_4-22,0546392645TTCTGTATACACCATCCC1-15-2TtctgtatacaccatcCC645_5-22,0046392645TTCTGTATACACCATCCC1-4-1-6-2-2-2TtctgTatacacCAtcCC645_6-25,1246392645TTCTGTATACACCATCCC1-3-1-8-1-1-3TtctGtatacaccAtCCC645_7-24,7346392645TTCTGTATACACCATCCC3-10-1-2-2TTCtgtatacaccAtcCC645_8-24,5246392645TTCTGTATACACCATCCC1-1-2-9-1-2-2TtCTgtatacaccAtcCC645_9-24,7146392645TTCTGTATACACCATCCC1-1-1-1-1-8-1-2-2TtCtGtatacaccAtcCC645_10-23,3446392646TTCTGTATACACCATCC1-10-1-3-2TtctgtatacaCcatCC646_1-19,9646393646TTCTGTATACACCATCC1-12-4TtctgtatacaccATCC646_2-21,1646393646TTCTGTATACACCATCC2-11-1-1-2TTctgtatacaccAtCC646_3-20,1146393646TTCTGTATACACCATCC1-2-1-9-1-1-2TtcTgtatacaccAtCC646_4-20,2446393646TTCTGTATACACCATCC1-3-1-8-1-1-2TtctGtatacaccAtCC646_5-19,5446393646TTCTGTATACACCATCC1-2-1-8-1-2-2TtcTgtatacacCatCC646_6-20,7746393646TTCTGTATACACCATCC1-12-1-1-2TtctgtatacaccAtCC646_7-19,2346393646TTCTGTATACACCATCC1-3-1-7-1-1-3TtctGtatacacCaTCC646_8-21,1946393646TTCTGTATACACCATCC1-1-1-1-1-10-2TtCtGtatacaccatCC646_9-20,4746393646TTCTGTATACACCATCC1-1-1-12-2TtCtgtatacaccatCC646_10-20,1646393646TTCTGTATACACCATCC1-1-1-11-3TtCtgtatacaccaTCC646_11-21,2846393646TTCTGTATACACCATCC1-3-1-9-3TtctGtatacaccaTCC646_12-20,6146393646TTCTGTATACACCATCC1-13-3TtctgtatacaccaTCC646_13-20,3046393646TTCTGTATACACCATCC3-1-1-10-2TTCtGtatacaccatCC646_14-21,9646393646TTCTGTATACACCATCC3-12-2TTCtgtatacaccatCC646_15-21,6546393646TTCTGTATACACCATCC1-1-2-11-2TtCTgtatacaccatCC646_16-21,8446393646TTCTGTATACACCATCC1-2-1-11-2TtcTgtatacaccatCC646_17-20,1946393646TTCTGTATACACCATCC1-3-1-10-2TtctGtatacaccatCC646_18-19,4946393646TTCTGTATACACCATCC1-14-2TtctgtatacaccatCC646_19-19,1846393646TTCTGTATACACCATCC3-8-1-3-2TTCtgtatacaCcatCC646_20-22,4446393646TTCTGTATACACCATCC1-3-1-6-1-3-2TtctGtatacaCcatCC646_21-20,2746393646TTCTGTATACACCATCC1-3-1-7-2-1-2TtctGtatacacCAtCC646_22-21,5346393646TTCTGTATACACCATCC1-1-1-9-1-2-2TtCtgtatacacCatCC646_23-20,7446393646TTCTGTATACACCATCC1-1-1-10-1-1-2TtCtgtatacaccAtCC646_24-20,2146393647AGCTTTTAACCAGAGT2-10-4AGcttttaaccaGAGT647_1-21,73EX-EX648AGCTTTTAACCAGAGTG2-11-4AGcttttaaccagAGTG648_1-22,27EX-EX649AGCTTTTAACCAGAGTGG1-14-3AgcttttaaccagagTGG649_1-21,63EX-EX650AGCTTTTAACCAGAGTGGC1-16-2AgcttttaaccagagtgGC650_1-23,20EX-EX651AGCTTTTAACCAGAGTGGCA1-17-2AgcttttaaccagagtggCA651_1-24,11EX-EX652CAGCTTTTAACCAGAGT2-12-3CAgcttttaaccagAGT652_1-21,65EX-EX653CAGCTTTTAACCAGAGTG3-13-2CAGcttttaaccagagTG653_1-22,27EX-EX654CAGCTTTTAACCAGAGTGG1-15-3CagcttttaaccagagTGG654_1-22,97EX-EX655CAGCTTTTAACCAGAGTGGC1-17-2CagcttttaaccagagtgGC655_1-24,53EX-EX656CTTTTAACCAGAGTG4-7-4CTTTtaaccagAGTG656_1-20,12EX-EX657CTTTTAACCAGAGTGG4-9-3CTTTtaaccagagTGG657_1-20,92EX-EX658CTTTTAACCAGAGTGGC4-11-2CTTTtaaccagagtgGC658_1-22,48EX-EX659CTTTTAACCAGAGTGGCA1-14-3CttttaaccagagtgGCA659_1-22,96EX-EX660CTTTTAACCAGAGTGGCAT3-13-3CTTttaaccagagtggCAT660_1-24,65EX-EX661CTTTTAACCAGAGTGGCATC2-16-2CTtttaaccagagtggca TC661_1-23,19EX-EX662GCTTTTAACCAGAGT3-9-3GCTtttaaccagAGT662_1-21,02EX-EX663GCTTTTAACCAGAGTG4-10-2GCTTttaaccagagTG663_1-21,02EX-EX664GCTTTTAACCAGAGTGG1-12-4GcttttaaccagaGTGG664_1-22,24EX-EX665GCTTTTAACCAGAGTGGC1-14-3GcttttaaccagagtGGC665_1-23,42EX-EX666GCTTTTAACCAGAGTGGCA1-16-2GcttttaaccagagtggCA666_1-22,94EX-EX667GCTTTTAACCAGAGTGGCAT1-16-3GcttttaaccagagtggCA T667_1-25,01EX-EX668TCAGCTTTTAACCAGAGT2-13-3TCagcttttaaccagAGT668_1-22,18EX-EX669TCAGCTTTTAACCAGAGTG2-14-3TCagcttttaaccagaGTG669_1-23,15EX-EX670TCAGCTTTTAACCAGAGTGG2-16-2TCagcttttaaccagagtGG670_1-23,41EX-EX671TTCAGCTTTTAACCAGAGT2-14-3TTcagcttttaaccagAGT671_1-22,72EX-EX672TTCAGCTTTTAACCAGAGTG2-15-3TTcagcttttaaccagaGTG672_1-23,69EX-EX673TTTCAGCTTTTAACCAGAGT2-15-3TTtcagcttttaaccagAGT673_1-23,66EX-EX674TTTT AACCAGAGTGGC1-11-4TtttaaccagagTGGC674_1-20,81EX-EX675TTTT AACCAGAGTGGCA3-11-3TTTtaaccagagtgGCA675_1-22,30EX-EX676TTTTAACCAGAGTGGCAT4-11-3TTTTaaccagagtggCAT676_1-23,21EX-EX677TTTTAACCAGAGTGGCATC4-13-2TTTTaaccagagtggcaTC677_1-22,57EX-EX678TTTTAACCAGAGTGGCATCC2-16-2TTttaaccagagtggcatCC678_1-24,58EX-EX679ATCAATATCTTCTCACT1-1-2-7-1-1-1-1-2AtCAatatcttCtCaCT679_1-19,165782679ATCAATATCTTCTCACT5-6-1-2-3ATCAAtatcttCtcACT679_2-21,495782679ATCAATATCTTCTCACT1-1-1-1-1-7-5AtCaAtatcttcTCACT679_3-20,185782679ATCAATATCTTCTCACT1-1-3-8-4AtCAAtatcttctCACT679_4-20,665782679ATCAATATCTTCTCACT3-10-1-1-2ATCaatatcttctCaCT679_5-18,625782680TATCAATATCTTCTCACT2-2-1-7-1-1-1-1-2TAtcAatatcttCtCaCT680_1-19,315782680TATCAATATCTTCTCACT1-1-2-8-1-1-1-1-2TaTCaatatcttCtCaCT680_2-19,895782680TATCAATATCTTCTCACT1-2-3-6-1-2-3TatCAAtatcttCtcACT680_3-20,665782680TATCAATATCTTCTCACT1-2-3-7-2-1-2TatCAAtatcttcTCaCT680_4-20,995782680TATCAATATCTTCTCACT2-1-1-10-4TAtCaatatcttctCACT680_5-20,895782681TATCAATATCTTCTCAC4-7-2-1-3TATCaatatctTCtCAC681_1-21,305783681TATCAATATCTTCTCAC1-2-2-6-2-1-3TatCAatatctTCtCAC681_2-19,735783681TATCAATATCTTCTCAC2-1-1-8-5TAtCaatatcttCTCAC681_3-20,265783681TATCAATATCTTCTCAC1-1-3-7-5TaTCAatatcttCTCAC681_4-21,745783681TATCAATATCTTCTCAC5-9-3TATCAatatcttctCAC681_5-20,835783682TTATCAATATCTTCTCAC1-1-1-1-2-6-2-2-2TtAtCAatatctTCtcAC682_1-18,325783682TTATCAATATCTTCTCAC1-3-1-8-5TtatCaatatcttCTCAC682_2-19,715783682TTATCAATATCTTCTCAC3-10-1-1-3TTAtcaatatcttCtCAC682_3-19,535783682TTATCAATATCTTCTCAC2-1-2-8-1-1-3TTaTCaatatcttCtCAC682_4-20,205783682TTATCAATATCTTCTCAC1-2-3-9-3TtaTCAatatcttctCAC682_5-19,475783683TTATCAATATCTTCTCACT1-1-1-1-1-8-1-1-1-1-2TtAtCaatatcttCtCaCT683_1-19,455782683TTATCAATATCTTCTCACT1-3-1-8-1-1-1-1-2TtatCaatatcttCtCaCT683_2-19,355782683TTATCAATATCTTCTCACT1-1-1-1-1-8-1-2-3TtAtCaatatcttCtcACT683_3-19,335782683TTATCAATATCTTCTCACT1-1-1-2-1-7-1-3-2TtAtcAatatcttCtcaCT683_4-18,185782683TTATCAATATCTTCTCACT1-1-1-2-1-9-4TtAtcAatatcttctCACT683_5-19,845782684ACCTTTCTTTAACCCTTT2-1-1-8-2-1-3ACcTttctttaaCCcTTT684_1-25,248113684ACCTTTCTTTAACCCTTT2-10-1-1-1-1-2ACctttctttaaCcCtTT684_2-22,318113684ACCTTTCTTTAACCCTTT1-1-1-9-1-1-1-1-2AcCtttctttaaCcCtTT684_3-22,018113684ACCTTTCTTTAACCCTTT1-1-1-1-1-9-1-1-2AcCtTtctttaaccCtTT684_4-21,538113684ACCTTTCTTTAACCCTTT1-1-1-11-1-1-2AcCtttctttaaccCtTT684_5-21,238113685TACCTTTCTTTAACCCTTT1-2-1-8-1-1-1-2-2TacCtttctttaAcCctTT685_1-22,448113685TACCTTTCTTTAACCCTTT1-2-1-1-1-7-1-1-1-1-2TacCtTtctttaaCcCtTT685_2-23,328113685TACCTTTCTTTAACCCTTT2-1-1-10-1-1-3TAcCtttctttaacCcTTT685_3-24,288113685TACCTTTCTTTAACCCTTT1-1-1-12-1-1-2TaCctttctttaaccCtTT685_4-22,138113685TACCTTTCTTTAACCCTTT1-2-1-11-1-1-2TacCtttctttaaccCtTT685_5-22,238113686ATACCTTTCTTTAACCC1-2-1-7-1-1-1-1-2AtaCctttcttTaAcCC686_1-20,538116686ATACCTTTCTTTAACCC1-3-1-6-1-3-2AtacCtttcttTaacCC686_2-20,218116686ATACCTTTCTTTAACCC2-2-1-7-2-1-2ATacCtttctttAAcCC686_3-21,898116686ATACCTTTCTTTAACCC1-1-1-1-1-8-1-1-2AtAcCtttctttaAcCC686_4-20,108116686ATACCTTTCTTTAACCC1-2-1-10-3AtaCctttctttaaCCC686_5-21,768116687ATACCTTTCTTTAACCCTT1-3-2-6-1-2-4AtacCTttctttAacCCTT687_1-26,108114687ATACCTTTCTTTAACCCTT1-1-1-1-1-8-1-1-1-1-2AtAcCtttctttaAcCcTT687_2-22,238114687ATACCTTTCTTTAACCCTT1-2-1-9-1-1-1-1-2AtaCctttctttaAcCcTT687_3-21,938114687ATACCTTTCTTTAACCCTT1-2-1-1-1-8-2-1-2AtaCcTttctttaaCCcTT687_4-24,418114687ATACCTTTCTTTAACCCTT1-3-1-11-3AtacCtttctttaaccCTT687_5-22,518114688ATACCTTTCTTTAACCCTTT1-3-1-8-1-1-1-2-2AtacCtttctttaAcCctTT688_1-22,838113688ATACCTTTCTTTAACCCTTT1-3-1-9-1-1-1-1-2AtacCtttctttaaCcCtTT688_2-23,418113688ATACCTTTCTTTAACCCTTT1-4-2-7-1-2-3AtaccTTtctttaaCccTTT688_3-23,988113688ATACCTTTCTTTAACCCTTT1-1-1-1-1-10-1-1-3AtAcCtttctttaacCcTTT688_4-23,638113688ATACCTTTCTTTAACCCTTT1-2-1-12-1-1-2AtaCctttctttaaccCtTT688_5-22,528113689ATACCTTTCTTTAACCCT1-3-2-6-2-2-2AtacCTttctttAAccCT689_1-22,618115689ATACCTTTCTTTAACCCT1-1-1-1-2-8-1-1-2AtAcCTttctttaaCcCT689_2-22,858115689ATACCTTTCTTTAACCCT1-2-1-10-1-1-2AtaCctttctttaaCcCT689_3-21,368115689ATACCTTTCTTTAACCCT1-2-3-10-2AtaCCTttctttaaccCT689_4-24,268115689ATACCTTTCTTTAACCCT1-3-1-11-2AtacCtttctttaaccCT689_5-20,698115690TATACCTTTCTTTAACCCT2-2-1-10-1-1-2TAtaCctttctttaaCcCT690_1-23,608115690TATACCTTTCTTTAACCCT1-4-1-9-1-1-2TatacCtttctttaaCcCT690_2-22,578115690TATACCTTTCTTTAACCCT2-3-1- 11-2TAtacCtttctttaaccCT690_3-22,928115690TATACCTTTCTTTAACCCT1-3-1-12-2TataCctttctttaaccCT690_4-21,688115690TATACCTTTCTTTAACCCT1-4-1-11-2TatacCtttctttaaccCT690_5-21,798115691TTATACCTTTCTTTAAC4-7-2-2-2TTATacctttcTTtaAC691_1-18,498118691TTATACCTTTCTTTAAC3-8-1-1-4TTAtacctttcTtTAAC691_2-18,078118692TTATACCTTTCTTTAACCC2-10-1-1-1-2-2TTatacctttctTtAacCC692_1-21,948116692TTATACCTTTCTTTAACCC1-1-1-9-1-4-2TtAtacctttctTtaacCC692_3-20,688116692TTATACCTTTCTTTAACCC1-4-1-7-1-3-2TtataCctttcttTaacCC692_3-21,798116692TTATACCTTTCTTTAACCC1-3-2-8-2-1-2TtatACctttctttAAcCC692_4-22,398116692TTATACCTTTCTTTAACCC1-1-1-2-1-9-1-1-2TtAtaCctttctttaAcCC692_5-21,588116693TTATACCTTTCTTTAACC2-3-1 - 6-1-3-2TTataCctttctTtaaCC693_1-19,808117693TTATACCTTTCTTTAACC1-1-1-1-2-6-1-3-2TtAtACctttctTtaaCC693_2-19,258117693TTATACCTTTCTTTAACC1-3-2-7-2-1-2TtatACctttcttTAaCC693_3-20,748117693TTATACCTTTCTTTAACC1-1-1-2-1-7-1-2-2TtAtaCctttcttTaaCC693_4-19,088117693TTATACCTTTCTTTAACC1-2-1-1-1-8-4TtaTaCctttctttAACC693_5-20,268117694TTTATACCTTTCTTTAACC2-1-1-8-2-3-2TTtAtacctttcTTtaaCC694_1-20,728117694TTTATACCTTTCTTTAACC1-4-1-6-1-2-4TttatAcctttcTttAACC694_2-20,338117694TTTATACCTTTCTTTAACC2-11-1-1-1-1-2TTtatacctttctTtAaCC694_3-19,728117694TTTATACCTTTCTTTAACC1-1-2-9-1-3-2TtTAtacctttctTtaaCC694_4-20,658117694TTTATACCTTTCTTTAACC1-3-2-7-1-3-2TttaTAcctttctTtaaCC694_5-20,888117695TTTATACCTTTCTTTAAC3-9-3-1-2TTTatacctttcTTTaAC695_1-18,748118695TTTATACCTTTCTTTAAC5-7-2-2-2TTTATacctttcTTtaAC695_2-20,318118695TTTATACCTTTCTTTAAC1-1-3-7-2-2-2TtTATacctttcTTtaAC695_3-18,988118695TTTATACCTTTCTTTAAC4-8-1-1-4TTTAtacctttcTtTAAC695_4-19,898118695TTTATACCTTTCTTTAAC2-3-1- 7-5TTtatAcctttctTTAAC695_5-18,028118696TTTTATACCTTTCTTTAAC2-3-1-6-3-2-2TTttaTacctttCTTtaAC696_1-19,798118696TTTTATACCTTTCTTTAAC1-1-2-8-2-1-1-1-2TtTTatacctttCTtTaAC696_2-19,578118696TTTTATACCTTTCTTTAAC2-1-2-7-2-2-3TTtTAtacctttCTttAAC696_3-20,288118696TTTTATACCTTTCTTTAAC3-9-1-1-5TTTtatacctttCtTTAAC696_4-20,628118696TTTTATACCTTTCTTTAAC1-1-3-7-1-1-1-2-2TtTTAtacctttCtTtaAC696_5-19,088118697TGTACTTTCCTTTACCA2-9-1-3-2TGtactttcctTtacCA697_1-20,6811462697TGTACTTTCCTTTACCA1-2-1-7-1-3-2TgtActttcctTtacCA697_2-19,6611462697TGTACTTTCCTTTACCA1-3-1-6-1-3-2TgtaCtttcctTtacCA697_3-20,4611462697TGTACTTTCCTTTACCA2-2-1-8-1-1-2TGtaCtttcctttAcCA697_4-21,5611462697TGTACTTTCCTTTACCA1-3-1-9-3TgtaCtttcctttaCCA697_5-22,5411462698TTATACACCATCATTAT4-7-3-1-2TTATacaccatCATtAT698_1-21,1311506698TTATACACCATCATTAT4-7-2-1-3TTATacaccatCAtTAT698_2-21,6411506698TTATACACCATCATTAT3-8-1-1-4TTAtacaccatCaTTAT898_3-19,4511506698TTATACACCATCATTAT2-1-2-7-5TTaTAcaccatcATTAT698_4-20,6111506698TTATACACCATCATTAT5-9-3TTATAcaccatcatTAT698_5-20,7411506699TTATACACCATCATTATA3-2-1-6-2-2-2TTAtaCaccatcATtaTA699_1-19,3811505699TTATACACCATCATTATA1-2-3-6-1-1-4TtaTACaccatcAtTATA699_2-20,9311505699TTATACACCATCATTATA4-1-1-7-2-1-2TTATaCaccatcaTTaTA699_3-21,4411505699TTATACACCATCATTATA2-1-2-8-1-1-3TTaTAcaccatcaTtATA699_4-19,7111505699TTATACACCATCATTATA3-2-1-8-4TTAtaCaccatcatTATA699_5-20,7511505700TTTATACACCATCATTAT2-1-2-7-3-1-2TTtATacaccatCATtAT700_1-20,6711506700TTTATACACCATCATTAT3-1-1-7-2-1-3TTTaTacaccatCAtTAT700_2-21,5211506700TTTATACACCATCATTAT1-3-2-6-2-1-3TttaTAcaccatCAtTAT700_3-20,7011506700TTTATACACCATCATTAT1-1-3-8-1-1-3TtTATacaccatcAtTAT700_4-20,0511506700TTTATACACCATCATTAT3-1-1-9-4TTTaTacaccatcaTTAT700_5-20,3411506701TTTATACACCATCATTATA4-8-1-1-2-1-2TTTAtacaccatCaTTaTA701_1-21,5711505701TTTATACACCATCATTATA2-2-1-7-1-2-4TTtaTacaccatCatTATA701_2-21,0511505701TTTATACACCATCATTATA1-1-1-1-1-8-2-1-3TtTaTacaccatcATtATA701_3-19,8311505701TTTATACACCATCATTATA2-2-2-7-2-2-2TTtaTAcaccatcATtaTA701_4-20,2411505701TTTATACACCATCATTATA1-1-3-10-1-1-2TtTATacaccatcatTaTA701_5-20,3011505702ATTTATACACCATCATTAT1-1-1-2-1-7-3-1-2AtTtaTacaccatCATtAT702_1-20,0711506702ATTTATACACCATCATTAT1-1-2-1-1-7-2-2-2AtTTaTacaccatCAttAT702_2-20,0711506702ATTTATACACCATCATTAT2-1-2-8-1-1-1-1-2ATtTAtacaccatCaTtAT702_3-19,7411506702ATTTATACACCATCATTAT2-3-1 - 7-1-2-3ATttaTacaccatCatTAT702_4-20,0711506702ATTTATACACCATCATTAT1-1-1-1-1-10-4AtTtAtacaccatcaTTAT702_5-18,6411506703ATTTATACACCATCATTATA1-4-1-7-1-2-4AtttaTacaccatCatTATA703_1-21,0511505703ATTTATACACCATCATTATA2-1-1-2-1-7-2-2-2ATtTatAcaccatcATtaTA703_2-20,3211505703ATTTATACACCATCATTATA1-1-1-2-1-8-1-1-1-1-2AtTtaTacaccatcAtTaTA703_3-18,8011505703ATTTATACACCATCATTATA1-2-3-8-1-1-1-1-2AttTATacaccatcAtTaTA703_4-21,1711505703ATTTATACACCATCATTATA3-1-1-9-1-2-3ATTtAtacaccatcAttATA703_5-19,9711505704TATTTATACACCATCATTA1-2-3-6-2-3-2TatTTAtacaccATcatTA704_1-20,3711507704TATTTATACACCATCATTA4-8-1-1-2-1-2TATTtatacaccAtCAtTA704_2-21,7011507704TATTTATACACCATCATTA1-1-1-1-1-7-1-1-1-1-3TaTtTatacaccAtCaTTA704_3-19,1611507704TATTTATACACCATCATTA2-2-1-8-2-2-2TAttTatacaccaTCatTA704_4-19,9811507704TATTTATACACCATCATTA2-2-1-10-4TAttTatacaccatcATTA704_5-19,9911507705TATTTATACACCATCATTAT2-2-1-1-1-7-2-2-2TAttTaTacaccatCAttAT705_1-21,4911506705TATTTATACACCATCATTAT2-1-1-10-1-1-4TAtTtatacaccatCaTTAT705_2-21,4411506705TATTTATACACCATCATTAT1-1-1-2-1-8-1-1-1-1-2TaTttAtacaccatCaTtAT705_3-18,2711506705TATTTATACACCATCATTAT2-1-2-9-1-3-2TAtTTatacaccatCattAT705_4-19,9711506705TATTTATACACCATCATTAT1-2-3-9-1-1-3TatTTAtacaccatcAtTAT705_5-21,1111506706TTATTTATACACCATCATTA2-3-1-7-1-1-1-1-3TTattTatacaccAtCaTTA706_1-20,5411507706TTATTTATACACCATCATTA1-1-2-1-1-7-1-2-4TtATtTatacaccAtcATTA706_2-20,8411507706TTATTTATACACCATCATTA1-1-1-2-1-8-2-2-2TtAttTatacaccaTCatTA706_3-19,5211507706TTATTTATACACCATCATTA1-2-3-8-1-1-1-1-2TtaTTTatacaccaTcAtTA706_4-19,9611507706TTATTTATACACCATCATTA3-1-1-11-1-1-2TTAtTtatacaccatcAtTA706_5-19,6311507707ATTATTTATACACCATCAT2-2-2-6-3-2-2ATtaTTtatacaCCAtcAT707_1-22,4111509707ATTATTTATACACCATCAT2-3-1 - 6-1-2-4ATtatTtatacaCcaTCAT707_2-21,0211509707ATTATTTATACACCATCAT1-1-1-1-1-8-3-1-2AtTaTttatacacCATcAT707_3-20,0111509707ATTATTTATACACCATCAT1-1-2-1-1-7-1-2-3AtTAtTtatacacCatCAT707_4-20,3011509707ATTATTTATACACCATCAT2-1-2-9-1-1-3ATtATttatacaccAtCAT707_5-20,2011509708ATTATTTATACACCATCA2-2-2-6-2-2-2ATtaTTtatacaCCatCA708_1-20,9611510708ATTATTTATACACCATCA3-1-1-7-1-1-4ATTaTttatacaCcATCA708_2-21,1911510708ATTATTTATACACCATCA1-1-3-7-1-3-2AtTATttatacaCcatCA708_3-19,3911510708ATTATTTATACACCATCA1-1-1-2-1-7-2-1-2AtTatTtatacacCAtCA708_4-18,5711510708ATTATTTATACACCATCA2-1-2-8-1-1-3ATtATttatacacCaTCA708_5-19,7911510709ATTATTTATACACCATCATT1-2-3-7-1-1-2-1-2AttATTtatacacCaTCaTT709_1-20,9711508709ATTATTTATACACCATCATT1-1-1-2-2-6-1-4-2AtTatTTatacacCatcaTT709_2-19,2911508709ATTATTTATACACCATCATT1-1-1-2-1-8-2-1-3AtTatTtatacaccATcATT709_3-19,7011508709ATTATTTATACACCATCATT3-1-1-9-1-1-1-1-2ATTaTttatacaccAtCaTT709_4-20,0911508709ATTATTTATACACCATCATT2-1-2-1-1-7-1-2-3ATtATtTatacaccAtcATT709_5-20,6711508710ATTATTTATACACCATC5-6-3-1-2ATTATttatacACCaTC710_1-21,7011511710ATTATTTATACACCATC5-6-2-1-3ATTATttatacACcATC710_2-20,3811511710ATTATTTATACACCATC2-2-1-7-5ATtaTttatacaCCA TC710_3-20,2511511710ATTATTTATACACCATC1-1-2-8-5AtTAtttatacaCCATC710_4-20,4211511710ATTATTTATACACCATC5-8-4ATTATttatacacCATC710_5-21,0411511711AATTATTTATACACCATC2-2-2-6-3-1-2AAttATttatacACCaTC711_1-18,9311511711AATTATTTATACACCATC2-1-3-6-1-1-4AAtTATttatacAcCATC711_2-20,1811511711AATTATTTATACACCATC4-1-1-7-5AATTaTttatacaCCATC711_3-22,2411511711AATTATTTATACACCATC2-1-2-8-5AAtTAtttatacaCCATC711_4-21,1711511711AATTATTTATACACCATC1-1-4-7-2-1-2AaTTATttatacaCCaTC711_5-20,5811511712AATTATTTATACACCATCA1-2-1-1-1-6-3-2-2AatTaTttatacACCatCA712_1-20,4211510712AATTATTTATACACCATCA2-2-1-7-1-1-2-1-2AAttAtttatacAcCAtCA712_2-18,5411510712AATTATTTATACACCATCA1-1-3-7-1-2-4AaTTAtttatacAccATCA712_3-20,6711510712AATTATTTATACACCATCA2-1-2-8-2-1-3AAtTAtttatacaCCaTCA712_4-22,2011510712AATTATTTATACACCATCA3-1-1-8-1-2-3AATtAtttatacaCcaTCA712_5-19,5011510713AAATTATTTATACACCATC3-2-1-6-3-1-3AAAttAtttataCACcATC713_1-19,2111511713AAATTATTTATACACCATC1-2-3-6-3-2-2AaaTTAtttataCACcaTC713_2-20,0111511713AAATTATTTATACACCATC1-1-3-7-2-1-4AaATTatttataCAcCATC713_3-21,6811511713AAATTATTTATACACCATC2-1-2-7-1-1-2-1-2AAaTTatttataCaCCaTC713_4-19,6311511713AAATTATTTATACACCATC1-1-2-1-1-8-5AaATtAtttatacaCCATC713_5-20,6711511714AAATTATTTATACACCAT1-1-4-6-2-1-3AaATTAtttataCAcCAT714_1-20,3111512714AAATTATTTATACACCAT2-2-2-6-1-1-4AAatTAtttataCaCCAT714_2-19,5911512714AAATTATTTATACACCAT1-1-3-7-1-1-4AaATTatttataCaCCAT714_3-20,0011512714AAATTATTTATACACCAT4-9-5AAA TtatttatacACCA T714_4-19,3611512714AAATTATTTATACACCAT3-1-2-7-5AAAtTAtttatacACCAT714_5-19,9811512715AAAATTATTTATACACCAT2-1-2-7-3-1-3AAaATtatttatACAcCAT715_1-19,2911512715AAAATTATTTATACACCAT1-3-2-6-2-1-4AaaaTTatttatACaCCAT715_2-19,6811512715AAAATTATTTATACACCAT3-2-1-6-1-1-5AAAatTatttatAcACCAT715_3-19,2711512715AAAATTATTTATACACCAT1-1-4-7-1-1-4AaAATTatttataCaCCAT715_4-20,7511512715AAAATTATTTATACACCAT2-1-2-9-5AAaATtatttatacACCAT715_5-19,3811512716TAAAATTATTTATACACC2-1-3-6-3-1-2TAaAATtatttaTACaCC716_1-18,8811514716TAAAATTATTTATACACC3-1-2-7-5TAAaATtatttatACACC716_2-18,9511514716TAAAATTATTTATACACC1-1-4-7-5TaAAATtatttatACACC716_3-18,3311514716TAAAATTATTTATACACC3-1-2-8-4TAAaATtatttataCACC716_4-18,3511514716TAAAATTATTTATACACC2-1-3-8-4TAaAATtatttataCACC716_5-18,3511514717GTAAAATTATTTATACACC2-1-3-6-4-1-2GTaAAAttatttATACaCC717_1-21,6811514717GTAAAATTATTTATACACC3-2-1-6-2-2-3GTAaaAttatttATacACC717_2-20,0011514717GTAAAATTATTTATACACC3-1-2-7-2-1-3GTAaAAttatttaTAcACC717_3-20,8611514717GTAAAATTATTTATACACC2-1-3-7-1-1-4GTaAAAttatttaTaCACC717_4-21,1111514717GTAAAATTATTTATACACC4-1-1-8-5GTAAaAttatttatACACC717_5-21,4611514718GTAAAATTATTTATACAC4-1-1-7-5GTAAaAttatttaTACAC718_1-18,1711515718GTAAAATTATTTATACAC3-1-2-7-5GTAaAAttatttaTACAC718_2-18,1711515719GAGTATATTACCTCCA3-10-3GAGtatattacctCCA719_1-22,5615162719GAGTATATTACCTCCA2-1-1-9-3GAgTatattacctCCA719_2-22,2415162719GAGTATATTACCTCCA2-11-3GAgtatattacctCCA719_3-21,1515162719GAGTATATTACCTCCA1-1-3-8-3GaGTAtattacctCCA719_4-22,9315162719GAGTATATTACCTCCA5-9-2GAGTAtattacctcCA719_5-23,2915162720CTTTTCTATAATCTCAC2-2-1-6-3-1 -2CTttTctataaTCTcAC720_1-18,5430553720CTTTTCTATAATCTCAC3-8-2-1-3CTTttctataaTCtCAC720_2-19,8030553720CTTTTCTATAATCTCAC1-1-3-6-1-1-4CtTTTctataaTcTCAC720_3-19,4030553720CTTTTCTATAATCTCAC4-8-5CTTTtctataatCTCAC720_4-21,3730553720CTTTTCTATAATCTCAC1-3-1-7-5CtttTctataatCTCAC720_5-18,9230553721CTTTTCTATAATCTCACA2-3-1- 6-1-1-1-1-2CTtttCtataatCtCaCA721_1-20,1730552721CTTTTCTATAATCTCACA1-1-1-1-2-6-1-2-3CtTtTCtataatCtcACA721_2-20,1530552721CTTTTCTATAATCTCACA1-2-1-1-1-7-2-1-2CttTtCtataatcTCaCA721_3-19,5030552721CTTTTCTATAATCTCACA1-1-3-8-1-1-3CtTTTctataatcTcACA721_4-19,4930552721CTTTTCTATAATCTCACA3-2-1-8-4CTTttCtataatctCACA721_5-21,9730552722TCTTTTCTATAATCTCACA1-1-3-7-1-1-1-1-3TcTTTtctataaTcTcACA722_1-21,0430552722TCTTTTCTATAATCTCACA1-4-1-6-1-2-1-1-2TctttTctataaTctCaCA722_2-18,8130552722TCTTTTCTATAATCTCACA2-2-1-8-1-2-3TCttTtctataatCtcACA722_3-20,6830552722TCTTTTCTATAATCTCACA2-1-1-9-1-3-2TCtTttctataatCtcaCA722_4-20,1330552722TCTTTTCTATAATCTCACA2-13-1-1-2TCttttctataatctCaCA722_5-19,5230552723TCTTTTCTATAATCTCAC2-1-1-8-2-2-2TCtTttctataa TCtcAC723_1-18,5130553723TCTTTTCTATAATCTCAC3-10-1-1-3TCTtttctataatCtCAC723_2-20,3630553723TCTTTTCTATAATCTCAC1-2-3-7-1-1-3TctTTTctataatCtCAC723_3-19,5730553723TCTTTTCTATAATCTCAC2-2-2-8-4TCttTTctataatcTCAC723_4-20,5730553723TCTTTTCTATAATCTCAC1-1-4-8-4TcTTTTctataatcTCAC723_5-20,8230553724ATCTTTTCTATAATCTCACA1-1-1-1-1-9-1-1-1-1-2AtCtTttctataatCtCaCA724_1-20,9330552724ATCTTTTCTATAATCTCACA1-1-1-11-1-2-3AtCttttctataatCtcACA724_2-20,5130552724ATCTTTTCTATAATCTCACA1-2-1-1-1-8-1-2-3AtcTtTtctataatCtcACA724_3-20,3530552724ATCTTTTCTATAATCTCACA1-3-2-8-1-3-2AtctTTtctataatCtcaCA724_4-20,1030552724ATCTTTTCTATAATCTCACA1-1-1-2-1-10-1-1-2AtCttTtctataatctCaCA724_5-19,9530552725ATCTTTTCTATAATCTCAC1-1-1-9-1-1-1-1-3AtCttttctataAtCtCAC725_1-19,6230553725ATCTTTTCTATAATCTCAC1-2-2-7-1-1-1-1-3AtcTTttctataAtCtCAC725_2-19,9730553725ATCTTTTCTATAATCTCAC1-1-2-1-1-7-2-2-2AtCTtTtctataaTCtcAC725_3-19,8330553725ATCTTTTCTATAATCTCAC1-2-1-1-1-9-4AtcTtTtctataatcTCAC725_4-19,3630553725ATCTTTTCTATAATCTCAC3-13-3ATCttttctataatctCAC725_5-20,2530553726ATCTTTTCTATAATCTCA1-1-2-8-1-1-1-1-2AtCTtttctataAtCtCA726_1-18,7730554726ATCTTTTCTATAATCTCA3-1-1-7-1-2-3ATCtTttctataAtcTCA726_ 2-20,0330554726ATCTTTTCTATAATCTCA3-10-2-1-2ATCttttctataaTCtCA726_3-20,3130554726ATCTTTTCTATAATCTCA1-1-1-1-2-7-2-1-2AtCtTTtctataaTCtCA726_4-19,4930554726ATCTTTTCTATAATCTCA1-1-3-9-4AtCTTttctataatCTCA726_5-21,1430554727CATCTTTTCTATAATCTCAC2-11-1-1-1-2-2CAtcttttctataAtCtcAC727_1-19,8630553727CATCTTTTCTATAATCTCAC1-1-2-9-1-1-1-2-2CaTCttttctataAtCtcAC727_2-20,4930553727CATCTTTTCTATAATCTCAC1-3-1-1-1-8-1-1-3CatcTtTtctataatCtCAC727_3-20,9730553727CATCTTTTCTATAATCTCAC1-2-1-1-1-9-1-2-2CatCtTttctataatCtcAC727_4-19,3530553727CATCTTTTCTATAATCTCAC2-1-1-2-1-10-3CAtCttTtctataatctCAC727_5-21,9230553728CATCTTTTCTATAATCTCA1-3-1-7-2-1-1-1-2CatcTtttctatAAtCtCA728_1-19,2630554728CATCTTTTCTATAATCTCA2-3-1 - 6-2-2-3CAtctTttctatAAtcTCA728_2-20,7430554728CATCTTTTCTATAATCTCA1-2-1-8-1-2-1-1-2CatCttttctatAatCtCA728_3-19,2130554728CATCTTTTCTATAATCTCA2-1-1-1-1-9-1-1-2CAtCtTttctataatCtCA728_4-20,8630554728CATCTTTTCTATAATCTCA1-1-2-13-2CaTCttttctataatctCA728_5-19,2330554729TCATCTTTTCTATAATCTCA1-1-1-2-1-7-2-1-1-1-2TcAtcTtttctatAAtCtCA729_1-20,5330554729TCATCTTTTCTATAATCTCA2-4-1-6-2-3-2TCatctTttctatAAtctCA729_2-20,5730554729TCATCTTTTCTATAATCTCA2-2-1-8-1-2-1-1-2TCatCttttctatAatCtCA729_3-21,7030554729TCATCTTTTCTATAATCTCA3-13-1-1-2TCAtcttttctataatCtCA729_4-22,0730554729TCATCTTTTCTATAATCTCA3-1-1-13-2TCAtCttttctataatctCA729_5-22,0730554730TCATCTTTTCTATAATCTC3-2-1-7-2-2-2TCAtcTtttctatAAtcTC730_1-20,1530555730TCATCTTTTCTATAATCTC3-1-1-8-1-3-2TCAtCttttctatAatcTC730_2-20,0930555730TCATCTTTTCTATAATCTC2-2-1-9-1-2-2TCatCttttctataAtcTC730_3-18,8330555730TCATCTTTTCTATAATCTC3-13-3TCAtcttttctataatCTC730_4-20,6530555730TCATCTTTTCTATAATCTC2-2-2-10-3TCatCTtttctataatCTC730_5-21,3530555731GTCATCTTTTCTATAATC1-1-1-2-1-6-3-1-2GtCatCttttctATAaTC731_1-19,7630557731GTCATCTTTTCTATAATC1-1-1-1-2-6-1-2-3GtCaTCttttctAtaATC731_2-19,1930557731GTCATCTTTTCTATAATC4-9-1-2-2GTCAtcttttctaTaaTC731_3-20,4230557731GTCATCTTTTCTATAATC3-2-1-8-4GTCatCttttctatAATC731_4-20,5130557731GTCATCTTTTCTATAATC1-1-4-10-2GtCATCttttctataaTC731_5-20,2330557732TGTCATCTTTTCTATAAT2-1-1-8-2-1-3TGtCatcttttcTAtAAT732_1-19,3630558732TGTCATCTTTTCTATAAT2-1-2-7-2-2-2TGtCAtcttttcTAtaAT732_2-20,5130558732TGTCATCTTTTCTATAAT1-1-3-7-1-3-2TgTCAtcttttcTataAT732_3-19,5130558732TGTCATCTTTTCTATAAT4-10-4TGTCatcttttctaTAAT732_4-21,4230558732TGTCATCTTTTCTATAAT2-2-1-9-4TGtcAtcttttctaTAAT732_5-18,5730558733ACTTAATTATACTTCCA5-6-2-2-2ACTT AattataCTtcCA733_1-21,5530664733ACTTAATTATACTTCCA2-1-2-6-1-2-3ACtTAattataCt...

Claims

1. An antisense oligonucleotide wherein the oligonucleotide is the oligonucleotide compound TTAcActtaattatactTCC (CMP ID NO: 626_7) wherein capital letters represent beta-D-oxy LNA nucleosides, lowercase letters represent DNA nucleosides, all LNA C are 5-methyl cytosine, and all internucleoside linkages are phosphorothioate internucleoside linkages.

2. A pharmaceutical composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable diluent, solvent, carrier, salt and / or adjuvant.

3. The pharmaceutical composition according to claim 2 wherein the pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS).

4. The pharmaceutical composition according to claim 2 or 3 wherein the pharmaceutically acceptable salt is a sodium salt.

5. The pharmaceutical composition according to claim 2 or 3 wherein the pharmaceutically acceptable salt is a potassium salt6. The pharmaceutical composition according to any one of claims 2 to 5 for use as a medicament.

7. An in vitro method for inducing UBE3A expression in a target cell where expression of paternal UBE3A is suppressed, said method comprising administering an oligonucleotide of claim 1 or the pharmaceutical composition of any one of claims 2 to 5 in an effective amount to said cell.

8. The method according to claim 7, wherein the expression of UBE3A is increased by at least 40% compared to a control.

9. The method according to claim 7 or 8, wherein the level of the SNHG14 transcript downstream of SNORD109B is reduced by at least 30% compared to a control.

10. The method according to any one of claims 7 to 9, wherein the target cell is a neuronal cell.

11. The method of any one of claims 7 to 10, wherein the expression of SNORD115 is not significantly affected compared to a control.

12. The oligonucleotide of claim 1 or the pharmaceutical composition of any one of claims 2 to 5 for use in the treatment or prevention of Angelman syndrome.